Systems and methods for mixing syringe valve assemblies

ABSTRACT

A syringe mixing system is provided for housing and mixing contents between at least two syringes. In some embodiments, a syringe coupler is provided that receives first and second syringes and includes a valve member that is convertible between a closed position and an open position. Retention systems for preventing or inhibiting removal of at least one syringe after use are also provided.

This U.S. Non-Provisional Patent Application is a Continuation of andclaims the benefit of priority of International ApplicationPCT/IB2021/062218, filed Dec. 22, 2021, and claims the benefit ofpriority of U.S. Provisional Patent Application Ser. No. 63/130,144,filed on Dec. 23, 2020, the entire disclosures of which are herebyincorporated by reference.

FIELD

The present disclosure relates generally to systems for mixing and tomixing syringes. More specifically, embodiments of the presentdisclosure relate to mixing syringes operable to store and selectivelymix contents between two syringes, and which include a valve assembly toseparate syringe contents at least prior to mixing operations.

BACKGROUND

It is known to store drugs and therapeutic agents in a lyophilized orpowdered form. For example, because of stability and shelf-life factors,therapeutic proteins are often formulated as powders that must bereconstituted, e.g. in a liquid or flowable medium or material, prior toinjection. Similarly, it is known to store components of certain complexdrug formulations (whether liquid or solid) in separate containers forreasons related to stability or reactivity of the components, where thecontents of the separate containers must be mixed prior to injection.Related methods and systems have been provided to allow users andhealthcare professionals to combine and formulate a drug just prior toadministration. Known systems and methods include single-barrel systemssuch as those shown and described in U.S. Pat. No. 9,592,343 to Shettyet al., which is hereby incorporated by reference. Such systems andmethods generally comprise two or more contents initially separated by avalved stopper or similar member and wherein repetitive motion of thestopper and associated plunger rod is operable to mix syringe contentsand subsequently eject a solution from the device. Dual-syringe systemsand methods are also known, such as those shown and described in U.S.Pat. No. 9,220,577 to Jessop et al, which is hereby incorporated byreference in its entirety. Dual-syringe systems generally comprise afirst material provided in a first syringe barrel and a second materialprovided in a second syringe barrel. The two syringe barrels of suchsystems can be connected to one another by joining their distal outletssuch that the two syringes are in fluid communication. Sequentialactivation of the plunger rods of each syringe is then operable to forcecontents between the two syringes and provide a mixing action.

However, various known systems and devices suffer from drawbacksincluding, for example, a high level of pre-administration steps thatcan increase the likelihood of user error, improper mixing, dosingerrors, and unwanted migration or leakage of syringe contents. Forexample, existing devices may initially be provided to a user as twoseparate syringes, each housing separate contents, e.g. a liquid orflowable component and a lyophilizate or other form of therapeuticagent, in order to reduce or eliminate the risk of unwanted migration ofthe liquid or flowable component from a first syringe to thelyophilizate or other form of therapeutic agent of a second syringeduring storage. However, the use of such a device requires additionalsteps, including assembly steps, before mixing and administration canoccur. Conversely, single-barrel systems reduce or eliminate the need toconnect or assemble components prior to mixing but provide for thepossibility that a liquid or flowable component can migrate or leak intoa volume containing lyophilizate or other form of therapeutic agentprior to the desired time for mixing. Single-barrel systems are alsorestricted by the viscosity of syringe contents and are not suitable forall applications.

SUMMARY

Accordingly, there has been a long-felt and unmet need to providemethods and systems for mixing drugs and therapeutic agents whilereducing the risks and drawbacks of methods and systems of the priorart.

It is an object of the present disclosure to provide methods and systemsfor mixing contents while reducing the number of required administrationsteps. It is also an object of the present disclosure to provide methodsand systems for mixing contents which reduce the risk of adverse usererrors and mistakes associated with administration of said contents. Itis a further object of the present disclosure to provide methods andsystems for mixing the contents of containers, chambers, or syringeswhile preventing or reducing the risk of unwanted migration,combination, mixing, etc. of materials. Furthermore, it is an object ofthe present disclosure to provide methods and systems for mixingportions of a pharmaceutical composition or formulation comprising anactive pharmaceutical ingredient (API) useful in the treatment in adisease or disorder in a patient. It is yet a further object of thepresent disclosure to provide methods and systems for mixing materialsof a pharmaceutical formulation comprising lyophilized leuprolide or apharmaceutically acceptable salt thereof (e.g. leuprolide acetate) and abiodegradable polymer-solvent system useful in the treatment of adisease or a disorder, including a cancer, including but not limited toprostate cancer or breast cancer.

In various embodiments, mixing syringe systems are provided comprising afirst syringe, a second syringe, and a syringe coupler or couplingdevice. The syringe coupler is contemplated as comprising a device thatis operable to interconnect the first and second syringe and tosegregate contents of the two syringes during shipping and storage, forexample, and which provides a reliable seal or closure element toachieve segregation while also obviating the need for users to assemblethe syringes prior to mixing. In some embodiments, a first syringe, asecond syringe, and a syringe coupler are provided and the componentsare interconnected for shipping and storage such that a user need notassemble components prior to mixing for subsequent administration of adrug or a therapeutic agent.

While various embodiments of the present disclosure contemplate a firstsyringe comprising first syringe contents (e.g. fluid) and a secondsyringe comprising second syringe contents (e.g. solid(s)), furtherembodiments contemplate that a first syringe may be initially devoid ofmaterial and a second syringe is provided that comprises one or morecontents that require mixing. It should be recognized that variousstoring, mixing, and reconstitution applications are contemplated byembodiments of the present disclosure and inventive aspects of thedisclosure are not limited to any particular intended use orapplication.

In some embodiments, a user-activated element is provided with systemsof the present disclosure. The user-activated element preferablycomprises an irreversible “one-way” feature wherein the user is allowedto activate the element and move the element from a first state to asecond state but cannot return the element to the first state. Forexample, in some embodiments, a valve activation element is providedthat is operable to be moved by a user from a first position (e.g. asealed position) to a second position (e.g. a flow-enabled position) butcannot perform a reverse operation to close the element (i.e. theoperation from a first position to a second position is irreversible).

In various embodiments, a syringe coupler or hub member is providedwherein at least one syringe can be connected to the syringe coupler andwherein removal of the syringe from the coupler is prevented or impeded.In some embodiments, for example, a first syringe comprising a polymeris operable to be connected and/or disconnected from a syringe couplerprior to activation or adjustment of the syringe coupler. Once thesyringe coupler has been activated (e.g. a fluid flow path in thecoupler has been opened), the first syringe is no longer capable ofbeing removed. Preventing removal of at least one syringe from thecoupler is useful, for example, to guide the user in the use of a secondsyringe (and only a second syringe) during administration once mixing iscompleted.

In various embodiments, systems and devices of the present disclosurecomprise an elastomer element operable to seal a fluid pathway betweenfirst and second syringes. It is contemplated that devices and systemsof the present disclosure are suitable for housing various materials andagents including, but not limited to: drugs and other therapeutic agents(in solid, e.g. lyophilized, or semi-solid or liquid/fluid form); liquidor flowable diluents, excipients or solvent systems; solvent systemsfurther comprising co-solvents; polymer-solvent systems; polymer-solventsystems comprising co-polymers; or any combination thereof. Anon-limiting example of a solvent suitable for use in the systems anddevices of the present disclosure is N-methyl-2-pyrrolidone (NMP), aliquid organic solvent with known volatility capable of producinggaseous vapor, which can circulate within enclosed spaces such as aninner plastic tray enclosure or outer carton commonly associated with adrug products packaging. While various embodiments of the presentdisclosure contemplate packaging and sealing elements with a secure sealfor various materials and uses, some embodiments contemplate and providesystems that securely house NMP or similar solvent and separate the NMPfrom a solid such as lyophilized leuprolide acetate. If NMP is allowedto migrate into a storage or housing area of the solid, the activepharmaceutical ingredient could be degraded such that shelf life andoverall stability of the materials are reduced. It should be recognizedthat other materials and applications stand to benefit from storage andsealing elements that provide a secure seal (at least prior to mixing)and the present disclosure is not limited to NMP and/or leuprolideacetate. Embodiments of the present disclosure as shown and describedherein provide for reliable physical separation and prevention ofmigration of vapor, liquids, and solids.

Various elastomers (e.g. santoprene) are contemplated for use with valveassemblies of embodiments of the present disclosure to inhibit orprevent liquid or gaseous solvent transmission. In further embodiments,it is contemplated that plastic components (including plastic-on-plasticcomponents) are provided that create sufficient sealing to preventliquid or gaseous solvent transmission between syringes and othercomponents of the present disclosure.

While various materials are contemplated for use with embodiments of thepresent disclosure, preferred embodiments of the present disclosurecontemplate the use of materials that are operable to withstand and arecompatible with terminal manufacturing sterilization using, e.g., e-beamirradiation, gamma radiation, x-ray techniques, and ethylene oxidesterilization.

In one embodiment, a syringe-to-syringe mixing system is provided thatcomprises a first syringe barrel comprising a hollow body defining aninternal chamber, and the hollow body has a proximal end and a distaldispensing end with an outlet. The system also comprises a secondsyringe barrel comprising a hollow body defining an internal chamber,the hollow body of the second syringe barrel having a proximal end and adistal dispensing end with an outlet. The first syringe barrel and thesecond syringe barrel each comprise a plunger slidably disposed withinthe syringe barrel for applying pressure to a content housed within theinternal chambers. A syringe coupler is provided that is operable toreceive the first syringe barrel and the second syringe barrel. Thesyringe coupler comprises a displaceable seal that comprises a flow portthat is offset from the outlet of at least one of the first syringebarrel and the second syringe barrel when the displaceable seal isprovided in a first position, and wherein the flow port is aligned withthe outlet of the first syringe barrel and the second syringe barrelwhen the displaceable seal is provided in a second position.

In another embodiment, a syringe-to-syringe mixing system is providedthat comprises a first syringe barrel with a hollow body, the hollowbody having a proximal end and a distal dispensing end with an outlet,and a second syringe barrel with a hollow body and an outlet, the secondsyringe comprising a distal dispensing end with an outlet. The firstsyringe barrel and the second syringe barrel each comprise a plungerslidably disposed within the syringe barrel for applying pressure to amaterial housed within the internal chambers. A valve assembly isprovided that is operable to receive the first syringe barrel and thesecond syringe barrel. The valve assembly comprises a displaceableuser-interface operable to receive a force from a user and transmit theforce to a displaceable seal, and wherein the displaceableuser-interface is moveable in a direction substantially perpendicular toa longitudinal axis of at least one of the first syringe barrel and thesecond syringe barrel.

In various embodiments, methods of mixing syringe contents and preparingtherapeutic agents are provided. In one embodiment, a method ofpreparing a therapeutic agent is provided that comprises providing afirst syringe barrel and a second syringe barrel. The first syringebarrel and the second syringe barrel each comprise a plunger slidablydisposed therein for applying pressure to a material housed within thesyringe barrels. A syringe coupler is provided that is operable toreceive the first syringe barrel and the second syringe barrel, and thesyringe coupler comprises a user-interface and a displaceable seal. Themethod comprises securing at least one of the first syringe barrel andthe second syringe barrel to the syringe coupler, applying a force tothe user-interface to move the displaceable seal from a first positionto a second position, and applying force to the plunger of the firstsyringe barrel and the second syringe barrel in an alternating manner tomix contents of the first syringe barrel and the second syringe barrel.

The Summary of the Invention is neither intended nor should it beconstrued as being representative of the full extent and scope of thepresent disclosure. The present disclosure is set forth in variouslevels of detail in the Summary as well as in the attached drawings andthe Detailed Description and no limitation as to the scope of thepresent disclosure is intended by either the inclusion or non-inclusionof elements, components, etc. in this Summary. Additional aspects of thepresent disclosure will become more readily apparent from the DetailedDescription, particularly when taken together with the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Those of skill in the art will recognize that the following descriptionis merely illustrative of the principles of the disclosure, which may beapplied in various ways to provide many different alternativeembodiments. This description is made for illustrating the generalprinciples of the teachings of this disclosure and is not meant to limitthe inventive concepts disclosed herein.

The accompanying drawings, which are incorporated in and constitute apart of the specification, illustrate embodiments of the disclosure andtogether with the general description of the disclosure given above andthe detailed description of the drawings given below, serve to explainthe principles of the disclosure.

It should be understood that the drawings are not necessarily to scale.In certain instances, details that are not necessary for anunderstanding of the disclosure or that render other details difficultto perceive may have been omitted. It should be understood, of course,that the disclosure is not necessarily limited to the particularembodiments illustrated herein.

FIG. 1 is a perspective view of a mixing syringe system.

FIG. 2A is a cut-away perspective view of a component of a mixingsyringe system according to one embodiment of the present disclosure.

FIG. 2B is a cut-away perspective view of a component of a mixingsyringe system according to one embodiment of the present disclosure.

FIG. 3 is an exploded perspective view of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 4A is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 4B is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 4C is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 5A is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 5B is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 5C is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 5D is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 6A is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 6B is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 7A is a cross-sectional elevation view of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 7B is a cross-sectional elevation view of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 8 is an elevation view of components of a mixing syringe systemaccording to an embodiment of the present disclosure.

FIG. 9 is an elevation view of components of a mixing syringe systemaccording to an embodiment of the present disclosure.

FIG. 10 is perspective view of a mixing system and associated packagingaccording to an embodiment of the present disclosure.

FIG. 11A is a cross-sectional elevation view of a component of a syringemixing system according to one embodiment of the present disclosure.

FIG. 11B is a cross-sectional elevation view of the component of FIG.11A in a second position.

FIG. 12A is a cross-sectional elevation view of a component of a syringemixing system according to one embodiment of the present disclosure.

FIG. 12B is a cross-sectional elevation view of the component of FIG.12A in a second position.

FIG. 12C is a side view of a component of a syringe mixing systemaccording to one embodiment of the present disclosure.

FIG. 12D is a front view of the component of the embodiment of FIG. 12C.

FIG. 12E provides front and side elevation views of the component of theembodiment of FIG. 12C.

FIG. 12F provides front and side elevation views of the component of theembodiment of FIG. 12C.

FIG. 13 is an exploded view of a syringe mixing system according to oneembodiment of the present disclosure.

FIG. 14A is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 14B is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 14C is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 15A is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 15B is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 15C is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 15D is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 16A is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 16B is a perspective view of a component of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 17A is a cross-sectional elevation view of a mixing syringe systemaccording to one embodiment of the present disclosure.

FIG. 17B is a cross-sectional elevation view of a mixing syringe systemaccording to one embodiment of the present disclosure.

DETAILED DESCRIPTION

FIG. 1 is a perspective view of a known syringe-to-syringe mixingsystem. As shown, the system 2 comprises a first syringe 4 housingcontents 6 and a second syringe 8 housing contents 10. The syringes 4, 8are connected at their respective distal dispensing ends. Fluid andmaterials housed within the syringes may be moved from one syringe toanother and mixing can occur by applying forces to the syringe plungerrods 12, 14. At least one plunger 16 is operable to force contentsbetween the syringes 4, 8 and produce a mixing action. Various knownsyringes and systems require the first syringe and second syringe to bedirectly connected (e.g. threaded together) by a user just prior tomixing and administration. The syringes are then disconnected with onesyringe comprising a mixed solution for administration.

FIGS. 2A-2B are perspective view of a component of a valve assembly fora mixing system contemplated for use with syringes according to oneembodiment of the present disclosure. As shown, a coupling element isprovided as a syringe coupler 18. The syringe coupler 18 comprises adevice that is operable to receive a first and second syringe andselectively provide the syringes in fluid communication with oneanother. The syringe coupler 18 comprises a first end 20 operable toreceive a first syringe and a second end 22 operable to receive a secondsyringe. The syringes (not shown in FIGS. 2A-2B) are contemplated ascomprising distal ends with open outlets for dispensing and/or receivingmaterials. FIGS. 2A-2B illustrate the first and second ends 20, 22 ascomprising female threaded connection members. It will be recognized,however, that syringe couplers of the present disclosure are not limitedto threaded connections and one or both of the first and second ends maycomprise alternative structure for receiving and securing syringes. Asfurther shown in FIGS. 2A-2B, the syringe coupler 18 comprise a valveelement comprising a displaceable member 24 that is moveable relative tothe coupler 18. First and second internal members 26, 28 are providedthat each comprise an aperture and which cooperate with the displaceablemember.

As shown in FIG. 2A, a closed position is provided wherein thedisplaceable member 24 is in a first position and a central aperture ofthe displaceable member is offset from the apertures of the first andsecond internal members 26, 28. In this position, fluid and gaseousvapor flow is at least partially and preferably fully occluded throughthe coupler. Accordingly, syringes connected to the coupler 18 cannotexchange materials in the closed position. The displaceable member 24 isoffset and preferably comprises a surface or user-interface that isaccessible to a user and operable to receive an activation force.

An activation force upon the displaceable member 24 is operable to movethe displaceable member from a first position (FIG. 2A) wherein fluidflow through the member 18 is occluded to a second position (FIG. 2B)wherein an aperture of the displaceable member 24 is aligned withapertures of the internal members 26, 28 and a fluid flow path is formedthrough the device. As shown and described the syringe coupler 18provides means for securing at least one and preferably two syringes,and comprises a valve element to selectively allow for transmission ofmaterials between syringes upon activation of the valve element by auser.

FIG. 3 is an exploded perspective view of a mixing syringe system 40according to another embodiment of the present disclosure. As shown, thesystem 40 comprises a first syringe 42 and a second syringe 44. Thefirst and second syringes are contemplated as initially comprising solidor liquid contents. For example, the first syringe 42 may house orcomprise a polymer-solvent system such as, but not limited to, abiodegradable polymer dissolved in NMP and the second syringe 44 maycomprise a drug lyophilizate such as, but not limited to, lyophilizedleuprolide acetate. Although the discussion of various embodiments ofthe present disclosure contemplates and refers to the first syringecomprising NMP and the second syringe comprising a drug lyophilizate, itwill be recognized that the disclosure is not limited to thatarrangement. Syringe contents may be altered, rearranged and substitutedwhile remaining within the scope of the inventions of the presentdisclosure. Indeed, inventive aspects of the present disclosure arebelieved to reside in features and components of the described systemregardless of which materials (or if any materials) are provided withinthe components.

Unwanted NMP migration (i.e. unintended migration prior to mixing) hasbeen recognized as providing various complications including, forexample, degrading or destroying shelf-life of contents. It is an objectof various embodiments of the present disclosure to reduce or eliminatethe risks of unwanted NMP migration while storing NMP and a druglyophilizate in close proximity prior to mixing.

The contents of the first and second syringes 42, 44 may be mixed toformulate a solution or suspension for administration as shown anddescribed herein. The embodiment of FIG. 3 comprises a syringe coupler46. The syringe coupler 46 of the depicted embodiment is operable toreceive and connect to the first and second syringes 42, 44, selectivelyprevent and enable fluid transfer between the two syringes, andselectively prevent removal of at least one syringe.

Each syringe 42, 44 comprises a barrel having an internal volume,proximal ends for receiving a plunger rod (not shown in FIG. 3), anddistal ends with dispensing outlets wherein the distal ends are operableto connect to the syringe coupler 46. The syringe coupler 46 comprises avalve assembly with a sealing element 48 that nests within recessed area51 of a displaceable member 50. In some embodiments, including thatshown in FIG. 3, the sealing element comprises an annular sealingelement. The displaceable member comprises a user-interface 52 that isoperable to be contacted by and receive a force from a user and a maleextension 54 for receiving the second syringe 44. The syringe coupler 46further comprises a guide member 56 within which the displaceable memberis provided. The guide member comprises a user-interface 57 (FIG. 5A)that is operable to be contacted by and receive a force from a user. Arotatable Luer lock member 58 is provided. The rotatable Luer lockmember 58 of the depicted embodiment comprises a proximal end with amale fitting operable to connect to the first syringe 42, and a distalend comprising a cog with teeth or projections for selectively limitingrotation of the rotatable Luer lock member 58 prior to activation.

FIGS. 4A-4C are perspective views showing the displaceable member 50 ingreater detail. As shown, the displaceable member 50 comprises auser-interface 52 operable to be acted upon by a user. In preferredembodiments, the displaceable member is displaceable in a downwarddirection (at least relative to FIG. 4A) and is preferably not operableto return to an initial or first position. A male extension 54 isprovided on one side of the member for receiving a syringe. A recess 56is provided on an opposing side of the displaceable member relative tothe male extension 54. The recess 56 is operable to receive a sealingelement, such as the annular sealing element 48 of FIG. 3. A channel isprovided through the displaceable member 50, wherein the channel extendsthrough the male extension 54 and into the recess 56. Preferably, asealing element comprises an aperture that is aligned with the channelof the displaceable member 50.

As shown in FIGS. 4A-4B, first and second projections 60, 75 areprovided on the displaceable member 50. The projections 60, 75 aredisplaceable with the member 50 and are moveable relative to at leastthe rotatable Luer lock member 58 of an assembled device. In a firstposition, at least one of the projections is provided in contact withthe rotatable Luer lock member 58 to prevent rotation of the member 58.This contact and related locking of the rotatable Luer lock member 58enables a first syringe to be threaded onto (and threadably removedfrom) the rotatable Luer lock member 58 prior to activation of theassembled device. Movement of the displaceable member 50 by useractivation results in displacing the projections 60, 75 such that theyare not in contact with the Luer lock member 58. With rotation of therotatable Luer lock member enabled, the member 58 is free to spin withinthe displaceable member 50. Without resistance, a syringe connected tothe rotatable Luer lock member 58 is prevented from being threadablydetached from the syringe coupler even if and when a rotation is appliedin an attempt to remove the syringe. It is an object of the presentdisclosure to provide a syringe coupler 46 that retains at least onesyringe such that a user is prevented from using the first syringe foradministration and is thereby only given the option of administering themixed contents with the second syringe.

As shown in FIGS. 4A-4C, the displaceable member 50 also comprises clipsor resilient projections 62 a, 62 b. The resilient projections 62 a, 62b are operable to flex outwardly and do not substantially impede adownward movement of the displaceable member 50. When provided in asecond position, however, the resilient projections 62 a, 62 b aresecured to the guide member 56 at least in part due to an inherentrestoring force of the projections. The resilient projections 62 a, 62 bsecure the displaceable member 50 in a second position within guidemember 56 through engagement of said resilient projections 62 a, 62 binto recesses 74 a, 74 b located upon guide member 56 to prevent orinhibit the displaceable member from being returned to a first position.

FIGS. 5A-5D are perspective views of a guide member 56 according to oneembodiment and contemplated for use and cooperation with thedisplaceable member 50 is FIGS. 4A-4C. As shown, the guide member 56comprises a central aperture 70 to permit fluid flow and to receive arotatable Luer lock member 58 of embodiments of the disclosure. Theguide member 56 is provided to slidably receive at least a portion of adisplaceable member 50. As shown, the guide member 56 comprises areceiving portion 76 with first and second slot members 78 a, 78 b toreceive a displaceable member 50. The guide member comprises auser-interface 57 that is operable to be contacted by and receive aforce from a user. In certain embodiments, and as shown in FIGS. 5A-5D,the user-interface 57 is contemplated as comprising a gripping orcontact surface having ridges to reduce slipping and provide ergonomicbenefits.

A surface of the guide member 56 comprises a channel 72 (FIG. 5B) toreceive and guide the movement of a ramp-like projection 60 of thedisplaceable member 50 (FIG. 4B, for example). During assembly of thesyringe device connector, the guide member 56 operably receives thedisplaceable member 50 such that projection 60 of the displaceablemember 50 contacts an upper surface of receiving portion 76 of the guidemember 56 (at least relative to the direction in FIG. 5B) to induce aphysical separation between the surface of the displaceable member 50and the receiving portion 76 of the guide member 76. The ramp-likeprojection 60 allows a distal surface of the annular sealing element 48nesting within recessed area 51 of the displaceable member 50 to slideover the distal surface of Luer lock member 58 nested within the centralaperture 70 of guide member 56. Once ramp-like projection 60 traversesthe distal surface of Luer lock member 58 nested within the centralaperture 70 of guide member 56, the projection 60 is operably receivedinto one of the plurality of teeth 86 of the Luer lock member 58.Operable engagement of ramp-like projection 60 into one of the pluralityof teeth 86 of the Luer lock member 58 collapses the physical separationinduced during crossing of the distal surface of Luer lock member 58such that the distal surface of the annular sealing element 48 nestedwithin recessed area 51 of the displaceable member 50 is brought intodirect contact with the distal surface of Luer lock member 58 within thecentral aperture 70 of guide member 56 causing the annular sealingelement 48 to compress. Once ramp-like projection 60 is operablyreceived into one of the plurality of teeth 86 of the Luer lock member58 and annular sealing element 48 is compressed, the assembled syringedevice connector is configured into the first position prior toactivation. The ramp-like projection 60 is operable to allow the guidemember 56 to translate over various irregular surface including, forexample, a central aperture of the Luer lock member 58.

In a first position prior to activation, the ramp-like projection 60 andthe projection 75 of the displaceable member 50 are provided incommunication with a rotatable Luer lock member 58 to prevent rotationthereof. In a second position subsequent to activation, the projection60 of the displaceable member 50 is displaced into the channel 72 ofguide member 56 while projection 75 of the displaceable member isdisplaced into the recessed area 73 (FIG. 9) on the guide member 56where the projections 60, 75 assume positions that do not contact orimpede rotation of the rotatable Luer lock member 58. The secondposition further comprises a position wherein a fluid flow channel iscreated. Specifically, an annular sealing element 48 provided within thedisplaceable member 50 is moved from a first position characterized by achannel of the annular sealing element 48 being offset from andpreventing flow between inlets and outlets of interconnected syringesand a second position characterized by the channel of the annularsealing element 48 being provided in axial alignment with the syringeoutlets and inlets.

As shown in FIGS. 5A-5B, for example, the guide member 56 furthercomprises recesses 74 a, 74 b that are operable to receive resilientprojections 62 a, 62 b of a displaceable member and secure the syringecoupler in a second position. The recesses 74 a, 74 b are operable toprevent or at least impede a user from returning the device to a firstposition after activation of the syringe coupler.

FIGS. 6A-6B are perspective views of a rotatable Luer lock member 58according to one embodiment of the present disclosure. As shown, therotatable Luer lock member 58 comprises a first end with a male Luerlock 80 that provides a means of attachment to a first syringe as wellas a fluid flow path through a central aperture 81 of the member 58. Themale Luer lock 80 is at least partially provided within a threadedfemale member 82 that is operable to threadingly engage a first syringe.A bearing surface 84 is provided on an exterior of the member 58. Thebearing surface 84 is operable to be provided in the central aperture 70of the guide member 56 and contact the guide member. The bearing surface84 of the rotatable Luer lock member 58 comprises a surface upon whichthe member 58 can rotate (when unlocked) and contact the centralaperture 70 of guide member 56. The rotatable Luer lock member 58further comprises a plurality of teeth 86 operable to act as lockingmembers and selectively prevent rotation of the rotatable Luer lockmember 58. Specifically, when a projection of the present disclosure (75of FIG. 4B, for example) is provided in a first position, the projection75 is provided in contact with at least one of the plurality of teeth 86such that rotation of the rotatable Luer lock member 58 (at least withrespect to the guide member 56 and the displaceable member 50) isprevented. The secured nature or state of the member 58 in the firstposition allows a user to thread a first syringe within the threadedfemale member 82. When the displaceable member is displaced as shown anddescribed herein, the projection 75 is moved away from the plurality ofteeth 86 of the rotatable Luer lock member 58 such that rotation isunopposed and the member 58 is allowed to rotate relative to the guidemember 56 and the displaceable member. This freedom of rotation preventsor at least inhibits the un-threading and removal of the first syringeas a rotation force applied to the syringe will cause a rotation of therotatable Luer lock member 58. With no significant oppositional force onthe rotatable Luer lock member 58 or threaded female member 82,un-threading will not occur and the first syringe is effectivelyprevented from being removed from the syringe coupler.

FIGS. 7A-7B are cross-sectional elevation views of a system according toan embodiment of the present disclosure. As shown and previouslydescribed, the system comprises a first syringe 42 and a second syringe44. The syringes 42, 44 are connected to a syringe coupler comprising adisplaceable member 50 with a user-interface 52, an annular sealingelement 48, a guide member 56, and a rotatable Luer lock member 58provided at least partially within the guide member 56. The system isshown as being provided in a first position in FIG. 7A. The firstposition comprises a position wherein the displaceable member andassociated annular sealing element 48 are provided offset from a centralaxis and passageway of the rotatable Luer lock member 58. Specifically afluid flow path 90 a of the second syringe 44, the male extension 54 ofthe displaceable member 50, and the sealing member 48 is offset from andnot in communication with a fluid flow path 90 b of the first syringe 42and the rotatable Luer lock member 58. Fluid and gaseous vapor flowbetween syringes 42, 44 is thus prevented.

FIG. 7B depicts the system in a second position wherein the displaceablemember 50 has been displaced by application of force upon theuser-interface 52 (for example). As shown, fluid pathway 90 a of FIG. 7Aand related components have been displaced such that a continuous fluidpathway 90 is provided and fluid flow between the first syringe 42 andsecond syringe 44 is enabled. Mixing of contents is thus enabled,wherein plunger rods (not shown in FIGS. 7A-7B) associated with thefirst and second syringes 42, 44 are operable to force contents betweenthe syringes.

Systems, devices and methods of the present disclosure are not limitedto any particular therapeutic agent(s), solution(s), suspension(s), gas,or a combination thereof. In some embodiments, for example, it iscontemplated that that one or more non-lyophilized materials areprovided in syringes of the present disclosure. In some embodiments, agas (e.g. Cobalt gas) is provided in a syringe for mixing with contentsof a second syringe. Such embodiments, including others, complete thatmixing syringe systems of the present disclosure comprisegas-impermeable materials to prevent gas permeation and migration.However, in certain preferred embodiments, a first syringe 42 isinitially provided with a liquid formulation component such as apolymer-solvent system and a second syringe is provided with an API,which may, in some non-limiting instances, be present as a lyophilizedpower. In such embodiments, the contents are stored separately with eachrespective syringe which are interconnected to the syringe coupler withthe displaceable member provided in the first position (FIG. 7A). Toadminister a therapeutic agent, the displaceable member is depressed orotherwise activated, creating the fluid-flow pathway 90 of FIG. 7B.Repetitive mixing may then be performed by forcing the polymer-solventof the first syringe 42 into the second syringe that comprises the API,forcing the contents back to the first syringe, and repeating theprocess until desired mixing is achieved. As discussed, the secondposition of FIG. 7B is characterized by the presence of a fluid flowpath between the two syringes 42, 44, as well as by the disengagement ofthe displaceable member 50 and the rotatable Luer lock member 58.Specifically, the second position (FIG. 7B) comprises a position inwhich the rotatable Luer lock member 58 is free to rotate within thesyringe coupler and the first syringe 42 is prevented from unthreadingor detachment. Accordingly, the second syringe 44 preferably comprisingthe mixed or prepared agent is detachable for use as an injectionsyringe while the first syringe is inoperable for such purposes.

FIG. 8 is an elevation view of components of a syringe coupler accordingto an embodiment of the present disclosure. As shown, a displaceablemember 50 and a guide member 56 are provided in a first position. Thefirst position is suitable for shipping and storage wherein fluid andgas vapor flow between interconnected syringes is fully or at leastpartially occluded. The displaceable member 50 comprises aninterconnected sealing element 48. The sealing element 48 comprises acentral aperture, but the central aperture is offset from the fluid flowpath of the guide member 56 and rotatable Luer lock member 58 such thatfluid flow through the device is occluded. The displaceable member 50and the guide member 56 comprise user-interface portions 52, 57,respectively. Force may be applied to one or more of the user-interfaces52, 57 to convert the device from the first position to a secondposition wherein the displaceable member 50 is displaced relative to theguide member and a fluid flow path is created (FIG. 7B, for example).

The displaceable member 50 comprises first and second projections 62 a,62 b that are operable to be outwardly displaced upon downward movementof the displaceable member. The first and second projections 62 a, 62 bare secured within the recesses 74 a, 74 b of the guide member 56 andmove inwardly based on their inherent material properties andelasticity. The placement of the first and second projections 62 a, 62 bwithin or partially within the recesses 74 a, 74 b of the guide member56 prevent or inhibit a return movement of the displaceable member 50back to the first position.

FIG. 9 is an elevation view of cooperating surfaces of a displaceablemember 50 and a guide member 56. As shown, the displaceable member 50comprises a ramp-like projection 60 that is operable to guideinstallation and interconnection of the displaceable member 50 and theguide member 56. A channel 72 is provided to receive and house theprojection 60. In a first position, rotation of a rotatable Luer lockingmember is substantially impeded by a second projection 75 being providedin contact with a portion of the Luer locking member. In a secondposition, the second projection 75 is displaced downwardly (at leastwith respect to FIG. 9) and the rotatable Luer locking member can freelyrotate within the aperture 70 of the guide member 56. The secondprojection 75 is provided on the displaceable member 50 and is operableto contact at least one of a plurality of teeth of a rotatable Luer lockmember 58 (not shown) in a first position and which is disposed intoslot 73 provided on the guide member 56 in a second position. Inaddition to locking and unlocking a rotatable Luer lock member 58 (notshown), the projection 75 of the displaceable member and thecorresponding features of the guide member 56 serve to limitdisplacement of the displaceable member and ensure that the displaceablemember comes to rest in a second position wherein a fluid flow path isaligned.

FIG. 10 is a perspective view of a syringe-to-syringe mixing systemprovided in packaging tray 100 according to one embodiment of thepresent disclosure. As shown, the system comprises a first and secondsyringe 42, 44 joined by a syringe coupler 46 including (for example)those shown and described herein. The syringes 42, 44 are connected tothe syringe coupler 46 for and during shipping and storage in apackaging member 100. The packaging member 100 of FIG. 10 comprises aclamshell device rotatable about a hinge 104 and in which the system isstored. Contours and indentations 102 of the packaging member 100 arecontemplated as being provided to restrict movement of certaincomponents of the system including, for example, unwanted movement of adisplaceable member (50 in FIG. 3, for example) and/or unwanted movementof syringe plunger rods. While various embodiments of the presentdisclosure contemplate the provision of first and second syringesattached to a syringe coupler for shipping and wherein the system isprovided to an end user in an assembled or interconnected state,alternative embodiments contemplate the provision of one or moresyringes initially detached from a syringe coupler. In such embodiments,a user such as a healthcare professional assembles the devices byconnecting one or more syringes to the syringe coupler just prior toconducting mixing operations.

FIG. 11A is a cross-sectional elevation view of a mixing syringecomponent 110 according to one embodiment of the present disclosure. Asshown, the component 110 comprises a valve element that is convertiblebetween a first position (FIG. 11A) and a second position (FIG. 11B). Asshown, the component 110 comprises first 112 and second 114 translatablecomponents. The first and second translatable components 112, 114 areoperable to be displaced relative to one another from a first position(FIG. 11A) wherein a conduit 116 of the first component 112 is unalignedwith a conduit 118 of the second component 114. In the first position,the conduits 116, 118 are not connected and fluid flow between thecomponents is substantially occluded. The first component 112 and secondcomponent 114 are displaceable to a second position (FIG. 11B) whereinthe conduits 116, 118 have been brought into connection and/or alignedsuch that fluid flow between the components 112, 114 is enabled.

In certain embodiments, proximal ends 120, 122 of the components areoperable to receive a syringe. An axial compression force on thesyringe(s) (not shown in FIGS. 11A-11B) is operable to displace thecomponents from the misaligned position of FIG. 11A to the alignedposition of FIG. 11B in which fluid is allowed to pass between thecomponents and related syringes. Although not shown in FIGS. 11A-11B,the proximal ends 120, 122 of the components are contemplated ascomprising securing means for syringes. Securing means are contemplatedas comprising, for example, threaded connection members, Luer lockcomponents, and similar features to selectively secure a syringe to thecomponents. In operation, a user may apply a compressive force to one ormore syringes connected to the mixing syringe component 110 of FIGS.11A-11B to displace the device from the position of FIG. 11A to themixing position of FIG. 11B. The user may then proceed with mixingoperations by sequentially applying a force to plunger rods ofinterconnected syringes as shown and described herein. The arrangementof the device of FIGS. 11A-11B therefore reduces process steps andreduces the need for a user to reposition their hands between activationof the valve element and a mixing operation.

It is further contemplated that the embodiments of FIGS. 11A-11Bcomprise stops or limiting members to prevent movement of the componentsbeyond a desired position wherein mixing is enabled. The limitingmembers may further comprise resilient stops or connection members tosecure the devices in a mixing position and prevent reverse translation.

FIG. 12A is a cross-sectional elevation view of a mixing syringecomponent 130 according to one embodiment of the present disclosure. Asshown, the component 130 comprises a valve element that is convertiblebetween a first position (FIG. 12A) and a second position (FIG. 12B). Asshown, the component 130 comprises first 132 and second 134 translatablecomponents. The first and second translatable components 132, 134 areoperable to be displaced relative to one another from a first position(FIG. 12A) wherein a conduit 136 of the first component 132 is unalignedwith a conduit 138 of the second component 134. In the first position,the conduits 136, 138 are not connected and fluid flow between thecomponents is substantially occluded. The first component 132 and secondcomponent 132 are displaceable to a second position (FIG. 12B) whereinthe components 132, 134 provide a ramped or cammed surface, and whereinthe conduits 132, 134 have been brought into connection and/or alignedsuch that fluid flow between the components 132, 134 is enabled.

In certain embodiments, proximal ends 140, 142 of the components areoperable to receive a syringe. An axial compression force on thesyringe(s) (not shown in FIGS. 12A-121B) is operable to displace thecomponents from the misaligned position of FIG. 12A to the alignedposition of FIG. 12B in which fluid is allowed to pass between thecomponents and related syringes. Although not shown in FIGS. 12A-12B,the proximal ends 140, 142 of the components are contemplated ascomprising securing means for syringes. Securing means are contemplatedas comprising, for example, threaded connection members, Luer lockcomponents, and similar features to selectively secure a syringe to thecomponents. In operation, a user may apply a compressive force to one ormore syringes connected to the mixing syringe component 130 of FIGS.12A-12B to displace the device from the position of FIG. 12A to themixing position of FIG. 12B. The user may then proceed with mixingoperations by sequentially applying a force to plunger rods ofinterconnected syringes as shown and described herein. The arrangementof the device of FIGS. 12A-12B therefore reduces process steps andreduces the need for a user to reposition their hands between activationof the valve element and a mixing operation.

It is further contemplated that the embodiments of FIGS. 12A-12Bcomprise stops or limiting members to prevent movement of the componentsbeyond a desired position wherein mixing is enabled. The limitingmembers may further comprise resilient stops or connection members tosecure the devices in a mixing position and prevent reverse translation.

FIG. 12C illustrates a mixing syringe component 300 operable toselectively permit and restrict a fluid flow through the device andassociated features. As shown, the component 300 comprises a valveelement having a first portion 302 and a second portion 304. Each of thefirst portion and the second portion comprise an aperture or flow port306 a, 306 b. When the flow ports 306 a, 306 b are offset or misalignedby a certain degree, flow through the component 300 is prevent. Thefirst portion 302 and second portion 304 are rotatable at least relativeto one another. Specifically, the portions 302, 304 are rotatable aroundan axis 308. A pin or axle member is contemplated as being provided tosecure the portions and enable rotation. FIG. 12C depicts the firstportion 302 and the second portion 304 in disassembled and assembledstates.

FIG. 12D is an elevation view of the component 300 of FIG. 12C. Thefirst portion 302 and the second portion 304 are rotationally offset toillustrate a motion and freedom of movement of the device 300. Arotational movement R is operable to place the first portion 302 and thesecond portion 304 in alignment and selectively enable fluid flow.

FIG. 12E shows the component 300 in a closed position wherein fluid flowis prevented or occluded. As shown, the second portion 304 is rotatedrelative to the first portion 302 such that the fluid flow ports 306 a,306 b are offset and fluid cannot pass through the device 300. Theposition shown in FIG. 12E is contemplated as being an initial positionwherein mixing and fluid flow are prevented.

FIG. 12F shows the component 300 in an aligned position wherein fluidflow is enabled. As shown, the first portion 302 and the second portion304 have been rotated into alignment wherein the flow ports 306 a, 306 bare axially aligned and a flow path 312 is created through the component300.

FIGS. 12C-12F contemplate and depict a device with portions that arerectilinear cubes. It will be recognized, however, that variousalternative arrangements are contemplated. For example, the first andsecond portions shown in FIGS. 12C-12F are also contemplated as beingprovided as disc-shaped features and/or various other geometric shapes.Additionally, although not shown in FIGS. 12C-12F, one or more stops ordétentes are contemplated as being provided to guide or limit an amountof relative rotation between the first portion and the second portion.For example, one or more stops are contemplated as being provided tosecured or lock the device in the open position (FIG. 12F, for example).Additionally, a ramp or resistance member is contemplated wherein aninitial resistance force is provided that must be overcome in order toopen the device and prevent or reduce the risk of accidental activation.

Although not shown in FIGS. 12C-12F, various extensions oruser-interface portions are contemplated. For example, the featuresshown in FIG. 12C-12F may be provided internal to or partially internalto a larger device, and an extension or trigger is provided to enable tocontrol rotation of at least a portion of the component 300.

FIG. 13 is an exploded perspective view of a mixing syringe system 150according to another embodiment of the present disclosure. As shown, thesystem 150 comprises a first syringe 152 and a second syringe 154. Thefirst and second syringes are contemplated as initially comprising solidor liquid contents. For example, the first syringe 152 may house orcomprise a polymer-solvent system such as, but not limited to, abiodegradable polymer dissolved in NMP and the second syringe 154 maycomprise lyophilizate such as, but not limited to, lyophilizedleuprolide acetate. Unwanted NMP migration (i.e. unintended migrationprior to mixing) has been recognized as providing various complicationsincluding, for example, degrading or destroying shelf-life of contents.It is an object of various embodiments of the present disclosure toreduce or eliminate the risks of unwanted NMP migration while storingNMP and a drug lyophilizate in close proximity prior to mixing.

The contents of the first and second syringes 152, 154 may be mixed toformulate a solution or suspension for administration as shown anddescribed herein. The embodiment of FIG. 13 comprises a syringe coupler156. The syringe coupler 156 of the depicted embodiment is operable toreceive and connect to the first and second syringes 152, 154,selectively prevent and enable fluid transfer between the two syringes,and selectively prevent removal of at least one syringe.

Each syringe 152, 154 comprises a barrel having an internal volume,proximal ends for receiving a plunger rod (not shown in FIG. 13), anddistal ends with dispensing outlets wherein the distal ends are operableto connect to the syringe coupler 156. The syringe coupler 156 comprisesa valve assembly with a sealing element 164 that nests within recessedarea 159 of a displaceable member 158. In some embodiments, includingthat shown in FIG. 13, the sealing element comprises a fluid impermeablematerial with an aperture to selectively allow fluid to flow through thedevice 156. The sealing element 164 of FIG. 13 comprises a rectilinearmember and is contemplated as having various shapes and sizes.

The displaceable member 158 comprises a user-interface 160 that isoperable to be contacted by and receive a force from a user and a maleextension 162 for receiving the second syringe 154. The syringe coupler156 further comprises a guide member 168 within which the displaceablemember is provided. The guide member 168 comprises a user-interface 178(FIG. 15C) that is operable to be contacted by and receive a force froma user. A rotatable member 166 is provided. The rotatable member 166 ofthe depicted embodiment comprises a rotatable Luer lock member with aproximal end with a male fitting operable to connect to the firstsyringe 152, and a distal end comprising a flange with a plurality ofcontact surfaces for limiting rotation of the rotatable member 166 priorto activation of the device.

FIGS. 14A-14C are perspective views showing the displaceable member 158in greater detail. As shown, the displaceable member 158 comprises auser-interface 160 operable to be acted upon by a user. In preferredembodiments, the displaceable member is displaceable in a downwarddirection (at least relative to FIG. 14A) and is preferably not operableto return to an initial or first position. A male extension 162 isprovided on one side of the member for receiving a syringe. A recess 159is provided on an opposing side of the displaceable member relative tothe male extension 162. The recess 159 is operable to receive a sealingelement, such as the sealing element 164 of FIG. 13. A channel isprovided through the displaceable member 158, wherein the channelextends through the male extension 162 and into the recess 159.Preferably, a sealing element comprises an aperture that is aligned withthe channel of the displaceable member 158.

As shown in FIGS. 14B-14C, a projection 170 is provided on thedisplaceable member 158. The projection 170 is displaceable with themember 158 and is moveable relative to at least the rotatable member 166of an assembled device. In a first position, the projection 170 isprovided in contact with a contact surface of the flange of therotatable member 166 to prevent rotation of the member 166. This contactand related locking of the rotatable member 166 enables a first syringeto be threaded onto (and threadably removed from) the rotatable member166 prior to activation of the assembled device. Movement of thedisplaceable member 158 by user activation results in displacing theprojection 170 such it is not in contact with rotatable locking member166. With rotation of the rotatable Luer lock member enabled, the member166 is free to spin within the syringe coupler. Without resistance, asyringe connected to the rotatable Luer lock member 166 is preventedfrom being threadably detached from the syringe coupler even if and whena rotation is applied in an attempt to remove the syringe. It is anobject of the present disclosure to provide a syringe coupler 156 thatretains at least one syringe such that a user is prevented from usingthe first syringe for administration and is thereby only given theoption of administering the mixed contents with the second syringe.

As shown in FIGS. 14A-4C, the displaceable member 158 also comprisesclips or resilient projections 172 a, 172 b. The resilient projections172 a, 172 b are operable to flex outwardly and do not substantiallyimpede a downward movement of the displaceable member 158. When providedin a second position, however, the resilient projections 172 a, 172 bare secured to the guide member 168 at least in part due to an inherentrestoring force of the projections. The resilient projections 172 a, 172b secure the displaceable member 158 in a second position within guidemember 168 through engagement of said resilient projections 172 a, 172 binto recesses 176 a, 176 b located upon guide member 168 to prevent orinhibit the displaceable member from being returned to a first position.

FIGS. 15A-15D are perspective views of a guide member 168 according toone embodiment and contemplated for use and cooperation with thedisplaceable member 158 is FIGS. 14A-14C. As shown, the guide member 168comprises a central aperture 174 to permit fluid flow and to receive arotatable Luer lock member 166 of embodiments of the disclosure. Theguide member 168 is provided to slidably receive at least a portion of adisplaceable member 158. As shown, the guide member 168 comprises areceiving portion 180 with first and second slot members 178 a, 178 b toreceive a displaceable member 158. The guide member comprises auser-interface 178 that is operable to be contacted by and receive aforce from a user. In certain embodiments, and as shown in FIGS.15A-15D, the user-interface 178 is contemplated as comprising a grippingor contact surface having ridges to reduce slipping and provideergonomic benefits.

A surface of the guide member 168 comprises a recessed area 182 in whichthe projection 170 of the displaceable member 158 (FIG. 14B, forexample) is allowed to translate. Specifically, when the coupler isactivated and the displaceable member 158 is displaced downwardlyrelative to the guide member 168, the projection 170 downwardly in therecessed area 182 to a second position wherein the projection 170 is notin contact with the rotatable member 166 regardless of the rotationalposition of the rotatable member 166.

The second position further comprises a position wherein a fluid flowchannel is created. Specifically, a sealing element 164 provided withinthe displaceable member 158 is moved from a first position characterizedby a channel of the sealing element 164 being offset from and preventingflow between inlets and outlets of interconnected syringes and a secondposition characterized by the channel of the sealing element 164 beingprovided in axial alignment with the syringe outlets and inlets.

As shown in FIGS. 15A-15B, for example, the guide member 168 furthercomprises recesses 176 a, 176 b that are operable to receive resilientprojections of a displaceable member and secure the syringe coupler in asecond position. The recesses are operable to prevent or at least impedea user from returning the device to a first position after activation ofthe syringe coupler.

FIGS. 16A-16B are perspective views of a rotatable member 166 accordingto one embodiment of the present disclosure. As shown, the rotatablemember 166 comprises a first end with a male Luer lock 200 that providesa means of attachment to a first syringe as well as a fluid flow paththrough a central aperture 202 of the member 166. The male Luer lock 200is at least partially provided within a threaded female member 204 thatis operable to threadingly engage a first syringe. A bearing surface 208is provided on an exterior of the member 166. The bearing surface 208 isoperable to be provided in the central aperture 174 of the guide member168 and contact the guide member. The bearing surface 208 of therotatable member 166 comprises a surface upon which the member 166 canrotate (when unlocked) and contact the central aperture 174 of the guidemember 168. The rotatable member 166 further comprises a flange 206 witha plurality of contact surfaces 207 to selectively prevent rotation ofthe rotatable member 166. Specifically, when a projection of the presentdisclosure (170 of FIG. 14B, for example) is provided in a firstposition, the projection 170 is provided in contact with at least onecontact surface 207 of the flange 206 and rotation of the member 166 isprevented (at least with respect to the guide member 168). The securednature or state of the member 166 in the first position allows a user tothread a first syringe within the threaded female member 204. When thedisplaceable member is displaced as shown and described herein, theprojection 170 is moved away from the flange 206 of the member 166 suchthat rotation is unopposed and the member 166 is allowed to rotaterelative to the guide member 168 and the displaceable member. Thisfreedom of rotation prevents or at least inhibits the un-threading andremoval of the first syringe as a rotation force applied to the syringewill cause a rotation of the rotatable member 166. With no significantoppositional force on the rotatable Luer lock member 166 or threadedfemale member 204, un-threading will not occur and the first syringe iseffectively prevented from being removed from the syringe coupler. Theflange 206 of the embodiment of FIGS. 16A-16B is depicted as a hexagonalflange. It will be recognized, however, that various alternative shapesand arrangements are contemplated that comprise at least one contactsurface for selectively preventing rotation of the member 166.

FIG. 16B shows the distal end of the channel 202 of the rotatable member166. As shown, the distal end 210 comprises a ramped or frustoconicalshape. The angled surface(s) of the distal end 210 allow for ease ofassembly of the device. Specifically, the distal end 210 is operable tocommunicate with a slot or ramp 171 of the displaceable member 158 (FIG.14C, for example). The angled nature of these corresponding featuresallows the guide member 168 comprising the rotatable member 166 to sliderelative to and be assembled with the displaceable member 158. Aspreviously discussed, the displaceable member is contemplated ascomprising a sealing member 164. In addition to facilitating ease ofassembly, the communication of the distal end 210 and the ramp 171 ofthe guide member provides for a temporary separation of the guide member168 and the displaceable member and avoid unwanted contact, damage, orsnagging of the seal 164 during assembly. Upon full insertion of thedisplaceable member 158 within the guide member 168, the distal end 210is provided proximal to the sealing member 164.

FIGS. 17A-17B are cross-sectional elevation views of a system accordingto an embodiment of the present disclosure. As shown and previouslydescribed, the system comprises a first syringe 152 and a second syringe154. The syringes 152, 154 are connected to a syringe coupler comprisinga displaceable member 158 with a user-interface 160, a sealing element164, a guide member 168, and a rotatable member 166 provided at leastpartially within the guide member 168. The system is shown as beingprovided in a first position in FIG. 17A. The first position comprises aposition wherein the displaceable member and associated sealing element164 are provided offset from a central axis and passageway of therotatable member 166. Specifically, a fluid flow path 190 a of thesecond syringe 154, the male extension of the displaceable member 158,and the sealing member 164 is offset from and not in communication witha fluid flow path 190 b of the first syringe 152 and the rotatablemember 166. Fluid and gaseous vapor flow between syringes is thusprevented.

FIG. 17B depicts the system in a second position wherein thedisplaceable member 158 has been displaced by application of force uponthe user-interface 160 (for example). As shown, fluid pathway 190 a ofFIG. 7A and related components have been displaced such that acontinuous fluid pathway 190 is provided and fluid flow between thefirst syringe 152 and second syringe 154 is enabled. Mixing of contentsis thus enabled, wherein plunger rods (not shown in FIGS. 17A-17B)associated with the first and second syringes are operable to forcecontents between the syringes.

Systems, devices and methods of the present disclosure are not limitedto any particular therapeutic agent(s), solution(s), suspension(s),gas(es), or a combination thereof. Various embodiments comprise featuresand sealing elements for preventing materials in at least one syringefrom escaping or migrating to another syringe. In some embodiments, forexample, it is contemplated that that one or more non-lyophilizedmaterials are provided in syringes of the present disclosure. In someembodiments, a gas (e.g. Nitrogen or Argon gas) is provided in a syringefor mixing with contents of a second syringe. Gas may be desirable, forexample, to be provided with an active pharmaceutical ingredient topreserve that ingredient during storage. Sealing elements of the presentdisclosure are operable to and suitable for maintaining gas in a syringeand preventing unwanted migration of that gas. Sealing elements are alsosuitable and operable for preventing escape or flow of liquids andsolids.

In some embodiments, mixing syringe systems of the present disclosurecomprise gas-impermeable materials to prevent gas permeation andmigration. However, in certain preferred embodiments, a first syringe152 is initially provided with a liquid formulation component (i.e.liquid or flowable material) such as a polymer-solvent system and asecond syringe is provided with an API, which may, in some non-limitinginstances, be present as a lyophilized power. In such embodiments, thecontents are stored separately with each respective syringe, which areinterconnected to the syringe coupler with the displaceable memberprovided in the first position (FIG. 17A). To administer a therapeuticagent, the displaceable member is depressed or otherwise activated,creating the fluid-flow pathway 190 of FIG. 17B. Repetitive mixing maythen be performed by forcing the polymer-solvent of the first syringe152 into the second syringe that comprises the API, forcing the contentsback to the first syringe, and repeating the process until desiredmixing is achieved. As discussed, the second position of FIG. 17B ischaracterized by the presence of a fluid flow path between the twosyringes, as well as by the disengagement of the displaceable member 158and the rotatable member 166. Specifically, the second position (FIG.17B) comprises a position in which the rotatable member 166 is free torotate within the syringe coupler and the first syringe 152 is preventedfrom unthreading or detachment. Accordingly, the second syringepreferably comprising the mixed or prepared agent is detachable for useas an injection syringe while the first syringe is inoperable for suchpurposes.

As disclosed herein, the syringe mixing system of the invention maycomprise methods and systems for mixing components of a pharmaceuticalcomposition or formulation comprising an API useful in the treatment ina disease or disorder in a patient. In some embodiments, the syringemixing system comprises a first syringe containing a first gas, liquid,or solid composition and a second syringe containing a second gas,liquid, or solid composition. Upon activation of the syringe connectorfrom a first, closed position to a second, open position, the first gas,liquid, or solid composition of the first syringe may be intermixed withthe second gas, liquid, or solid composition of the second syringe (orvice versa) until a desired intermixed composition is formed. In someinstances, the first or second syringe (but not both) may contain a gascomponent which may be an inert or volatile gas or gas vapor. In someinstances, the first and second syringe may contain an aqueous based ororganic based liquid which forms a solution, suspension, or both. Insome further instances of the disclosed invention, the first syringe maycomprise liquid formulation component or a solvent system which may, insome non-limiting examples, contain a biodegradable polymer dissolved orsuspended within an aqueous, organic, or intermixed aqueous-organicsolvent system, which may further contain additional co-solvents. Insome instances, the first or second syringe (but not both) may contain asolid which may be an API useful in the treatment of a disease ordisorder or amelioration of a symptom thereof. In some furtherinstances, the solid may be a lyophilized powder, semi-solidparticulate(s), or solid particulate(s) of varying sizes, shapes, andcharacteristics (e.g. specific surface area for example). Yet, furtherstill, in some other non-limiting instances, the first or second syringeof the syringe device system may comprise a lyophilized powder,semi-solid particulate(s), or solid particulate(s) of varying sizes,shapes, and characteristics (e.g. specific surface area for example)which may be prepared and/or stored within the first or second syringewithin the presence of a gas of choice, i.e. both lyophilized powder andgas are contained within the first or second syringe prior to mixingsaid components with the components stored within the opposing syringe,which may be, but is not necessarily limited to, a liquid of interest.

As disclosed herein, the syringe mixing system of the invention maycomprise methods and systems for mixing components of a pharmaceuticalcomposition or formulation comprising an API useful in the treatment ofa disease or condition in a patient. Such a syringe mixing system may bereferred to as a “prefilled syringe mixing system”, wherein the syringesof the syringe mixing system are prefilled with components of apharmaceutical composition or formulation that are then mixed togetherusing the syringe mixing system as described herein, such that the mixedpharmaceutical composition or formulation can then be administered to apatient in need of such pharmaceutical composition or formulation. Insome embodiments of the invention, the syringe mixing device (prefilledsyringe mixing system) may comprise a pharmaceutical formulationcomprising: (a) an API, which is contained within the first syringe, and(b) a biodegradable polymer-solvent system contained within the secondsyringe, which may be intermixed upon activation of the syringeconnector by a user such as to prepare a medication or medicament usefulin the treatment of a disease or condition by administration of themixed formulation into a patient in need thereof. The syringe mixingsystem can be used to store and then mix for administration anypharmaceutical composition or formulation that would benefit from theadvantages of the inventive syringe mixing system, and the disease orcondition to be treated will naturally depend on the drug or therapeuticagent included in the pharmaceutical composition or formulation.

In some embodiments, the API is a Gonadotrophin Releasing Hormone (GnRH)agonist or antagonist or a pharmaceutically acceptable salt thereof.Diseases or conditions that may be treated with a GnRH agonist orantagonist or a pharmaceutically acceptable salt thereof may include,but are not limited to, certain types of cancers, central precociouspuberty (CPP), endometriosis, or uterine fibroids. In some instances, acancer that may be treated with a GnRH agonist or antagonist or apharmaceutically acceptable salt thereof may include but is not limitedto prostate cancer (including but not limited to advanced prostatecancer) or breast cancer.

Leuprolide, as known as leuprorelin, is a synthetic peptide analog thatacts as a “super agonist” upon pituitary GnRH receptors. GnRH agonists,such as leuprolide or a pharmaceutically acceptable salt thereof (suchas leuprolide acetate), may be used in the treatment of prostate cancer(including advanced prostate cancer) in adult males, HR-positive breastcancer (including, but not limited, to HR-positive, human epidermalgrowth factor receptor 2 (HER2)-negative breast cancer) and CPP.Administration of GnRH agonists (or GnRH) leads to downregulation ofGnRH receptor activity, which in turn downregulates GnRH-dependentsecretion of gonadotropins, including but not limited to, luteinizinghormone (LH) and follicle-stimulating hormone (FSH). Downregulation ofLH and FSH leads to subsequent down-regulation of secondarysex-hormones, including but not limited to, testosterone and estradiol.Testosterone is a key metabolite in driving prostate cancer developmentand progression in adult males. As such, the reduction of serumtestosterone levels is a useful clinical approach for slowing orinhibiting the growth of prostate cancer. Likewise, clinical approachesthat modulate hormone activity and/or synthesis, particularly that ofestrogens (e.g. estradiol), are useful for slowing or inhibiting thegrowth of hormone receptor-positive (HR-positive) breast cancer.Controlled release formulations for the extended release of leuprolideuseful in the treatment of the prostate cancer in adult males, breastcancer, and CPP in pediatric patients 2 years old or older have beendeveloped. Controlled release formulations using flowable biodegradablepolymer based compositions for sustained, extended release of leuprolideor pharmaceutically acceptable salts thereof have been described, by wayof example, in U.S. Pat. Nos. 6,565,874 and 8,470,359, WO 2020/2404170,and WO 2020/217170, each of which are incorporated herein by referencein their entireties.

As disclosed herein, the syringe device or mixing system may be used tosubcutaneously administer an API to a patient in need thereof. In someembodiments, the API is a GnRH agonist or antagonist or apharmaceutically acceptable salt thereof and the patient may suffer fromprostate cancer, hormone receptor-positive breast cancer, or CPP. Insome embodiments, the method of administering the GnRH agonist orantagonist or the pharmaceutically acceptable salt thereof comprisesmixing a unit dose of the GnRH agonist or antagonist or thepharmaceutically acceptable salt thereof with a liquid formulationcomponent to form a reconstituted pharmaceutical composition using thesyringe-to-syringe mixing system; and administering the reconstitutedpharmaceutical composition to the patient via subcutaneous injection. Insome embodiments, the syringe-to-syringe mixing system comprises a firstsyringe barrel comprising the GnRH agonist or antagonist or thepharmaceutically acceptable salt thereof, a second syringe barrelcomprising the liquid formulation component, and a syringe couplercomprising a displaceable member, wherein the displaceable membercomprises a seal with a flow port that is offset from an outlet of atleast one of the first syringe barrel and the second syringe barrel whenthe displaceable member is provided in a first position, and wherein theflow port is aligned with the outlet of the first syringe barrel and thesecond syringe barrel when the displaceable member is provided in asecond position, and wherein the displaceable member is displaceable ina direction that is substantially perpendicular to a longitudinal axisof at least one of the first syringe barrel and the second syringebarrel. The mixing comprises applying a force to a user-interface tomove the displaceable seal from the first position to the secondposition and applying force to a plunger positioned in the first syringebarrel and a plunger positioned in the second syringe barrel in analternating manner to mix the contents of the first syringe barrel andthe second syringe barrel. In some instances, the GnRH agonist orantagonist or the pharmaceutically acceptable salt thereof is leuprolideor a pharmaceutically acceptable salt thereof, such as leuprolideacetate.

In one embodiment, a syringe device system comprises a composition,which when formulated according to the methods of using the syringedevice system as described herein to intermix two separated componentsof the composition prior to administration, may be useful in thepalliative treatment of prostate cancer, including the palliativetreatment of advanced prostate cancer in an adult male patient, whenadministered by subcutaneous injection about once every month (once permonth) to reduce the patient's serum testosterone level to less than orequal to 0.5 ng/mL. According to this embodiment, the syringe devicesystem comprises a first syringe containing an amount of a GnRH agonistor antagonist or a pharmaceutically acceptable salt thereof. In someinstances, the syringe device system comprises a first syringecontaining an amount of lyophilized leuprolide or a pharmaceuticallyacceptable salt thereof, such as lyophilized leuprolide acetate. In someinstances, the amount of leuprolide or a pharmaceutically acceptablesalt thereof in the delivered reconstituted product may be about 7.0 mgleuprolide free base equivalent. In some instances, the amount ofleuprolide acetate in the delivered reconstituted product may be about7.5 mg. As used herein, the term “free base equivalent” may refer to theconjugate base or deprotonated form of an amine containing compound orsubstance. For instance, about 7.0 mg of leuprolide represents the freebase equivalent of about 7.5 mg of leuprolide acetate. According to thisembodiment, the syringe device system comprises a second syringecontaining an amount of a polymer-solvent system comprising an amount ofa biodegradable polymer, which in some instances is apoly(D,L-lactide-co-glycolide) acid-initiated (i.e. PLGH) polymer,dissolved in a biocompatible solvent, which in some instances is NMP. Insome instances, the biodegradable PLGH polymer may comprise a lactide toglycolide ratio of about 50:50. In some instances, the PLGH polymer maycompromise a copolymer containing at least one carboxyl end group. Insome instances, the PLGH polymer has a weight average molecular weightfrom about 31 kDa to about 45 kDa. In some instances, the amount of PLGHpolymer in the delivered reconstituted product may be about 82.5 mg. Insome instances, the amount of NMP in the delivered reconstituted productis about 160 mg. The term “weight average molecular weight,” unlessotherwise specified, means a weight average molecular weight as measuredby a conventional gel permeation chromatography (GPC) instrument (suchas an Agilent 1260 Infinity Quaternary LC with Agilent G1362A RefractiveIndex Detector) utilizing polystyrene standards and tetrahydrofuran(THF) as the solvent.

According to the methods of activating the syringe device system, asdisclosed herein, the user, after first allowing the pre-assembledsyringe device system to equilibrate to room temperature and thenremoving it from its packaging, applies force to the user-interfaceportions 52 and 57 of the displaceable member 50 and the guide member56, respectively, to activate the syringe coupler from the first closedposition to the second open position. The user then applies a force tothe second plunger disposed slidably within the second syringe totransfer the polymer-solvent system housed within the internal chamberof the second syringe barrel through the open, activated syringe couplerand into the internal chamber of the first syringe housing thelyophilized leuprolide acetate. Upon contact of the polymer-solventsystem with the lyophilized leuprolide acetate, the leuprolide acetatewill largely remain in suspension, thus requiring mixing with thepolymer-solvent system to ensure that a homogeneous suspension is formedprior to administration. The user then applies a force to the firstplunger disposed slidably within the first syringe to transfer thepartially to fully mixed components back through the open syringecoupler and into the second syringe. The user will continue mixing thecontents back and forth from the first and second syringes for betweenabout 15 seconds and two minutes. In some instances, mixing iscontemplated as continuing for about 25 seconds, about 45 seconds, orabout 1 minute, equivalent to approximately 30-90 full back-and-forthcycles (and in some preferred embodiments, about 60 full back-and-forthcycles) to ensure that the lyophilized leuprolide acetate is fullysuspended within the polymer-solvent system. The fully formulatedcomposition is subsequently displaced into the second syringe at a finalinjection volume of about 0.25 mL and administered formulation weight ofabout 250 mg. The user then disconnects the second syringe containingthe therapeutic formulation from the syringe device by de-threadingattachment to the male extension 54 upon the displaceable member 50 ofthe syringe connector. The user then attaches a needle, for example an18G to 20G needle, to the distal dispensing outlet of the secondsyringe. The user then subcutaneously administers the full formulationdose to an adult male prostate cancer patient in need of treatmentthereof.

According to the methods of administering the GnRH agonist or antagonistor a pharmaceutically acceptable salt thereof to a patient with prostatecancer using the syringe device system disclosed herein, the methodcomprises subcutaneously administering at least one injection of apharmaceutic composition comprising a unit dose of a GnRH agonist orantagonist or a pharmaceutically acceptable salt thereof, once everymonth (once per month), to the patient to suppress the patient's serumtestosterone level to less than or equal to 0.5 ng/ml. Prior to theadministering, the pharmaceutic composition is reconstituted using thesyringe device system comprising a first syringe barrel comprising theGnRH agonist or antagonist or a pharmaceutically acceptable salt thereofand a second syringe barrel comprising a liquid formulation component,the first and second syringe barrels being interconnected via a syringecoupler comprising a displaceable seal, wherein the displaceable sealbeing operable to be axially displaced from a first position to a secondposition by a force applied to a plunger of the first syringe barrel,and wherein the first position comprises a position in which materialtransfer through the syringe coupler is occluded, and the secondposition comprises a position in which at least a portion of thedisplaceable seal is not secured to an interior surface of the syringecoupler and material transfer through the syringe coupler is permitted.The pharmaceutic composition is reconstituted by applying a force to auser-interface to move the displaceable seal from the first position tothe second position and applying force to a plunger positioned in thefirst syringe barrel and a plunger positioned in the second syringebarrel in an alternating manner to mix contents of the first syringebarrel and the second syringe barrel. In some instances, the GnRHagonist or antagonist or the pharmaceutically acceptable salt thereof isleuprolide or a pharmaceutically acceptable salt thereof, such asleuprolide acetate. In some instances, the GnRH agonist or antagonist orthe pharmaceutically acceptable salt thereof is leuprolide or apharmaceutically acceptable salt thereof, such as leuprolide acetate. Insome instances, the pharmaceutical composition comprises about 7.5 mg ofleuprolide acetate and N-methyl-2-pyrrolidone and a 50:50 poly(lacticacid-co-glycolic acid) (PLGA) copolymer having a weight averagemolecular weight from about 31 kDa to about 45 kDa and at least oneterminal carboxylic acid end group as the liquid formulation component.

In another embodiment, a syringe device system comprises a composition,which when formulated according to the methods of using the syringedevice system as described herein to intermix two separated componentsof the composition prior to administration, may be useful in thepalliative treatment of prostate cancer, including the palliativetreatment of advanced prostate cancer in an adult male patient, whenadministered by subcutaneous injection about once every three months(once per three months) to reduce the patient's serum testosterone levelto less than or equal to 0.5 ng/mL. According to this embodiment, thesyringe device system comprises a first syringe containing an amount ofa GnRH agonist or antagonist or a pharmaceutically acceptable saltthereof. In some instances, the syringe device system comprises a firstsyringe containing an amount of lyophilized leuprolide or apharmaceutically acceptable salt thereof, such as lyophilized leuprolideacetate. In some instances, the amount of leuprolide or apharmaceutically acceptable salt thereof in the delivered reconstitutedproduct may be about 21.0 mg leuprolide free base equivalent. In someinstances, the amount of leuprolide acetate in the deliveredreconstituted product may be about 22.5 mg. According to thisembodiment, the syringe device system comprises a second syringecontaining an amount of a polymer-solvent system comprising an amount ofa biodegradable polymer, which in some instances is apoly(D,L-lactide-co-glycolide) (i.e. PLG) polymer dissolved in abiocompatible solvent, which in some instances is NMP. In someinstances, the biodegradable PLG polymer may comprise a lactide toglycolide ratio of about 75:25. In some instances, the PLG polymer maybe initiated with hexanediol. In some instances, the PLG polymer maycompromise a copolymer containing two primary hydroxyl end groups. Insome instances, the PLG polymer has a weight average molecular weightrange of about 17 kDa to about 21 kDa. In some instances, the amount ofPLG polymer in the delivered reconstituted product may be about 158.6mg. In some instances, the amount of NMP in the delivered reconstitutedproduct is about 193.9 mg.

According to the methods of activating the syringe device system, asdisclosed herein, the user, after first allowing the pre-assembledsyringe device system to equilibrate to room temperature and thenremoving it from its packaging, applies force to the user-interfaceportions 52 and 57 of the displaceable member 50 and the guide member56, respectively, to activate the syringe coupler from the first closedposition to the second open position. The user then applies a force tothe second plunger disposed slidably within the second syringe totransfer the polymer-solvent system housed within the internal chamberof the second syringe barrel through the open, activated syringe couplerand into the internal chamber of the first syringe housing thelyophilized leuprolide acetate. Upon contact of the polymer-solventsystem with the lyophilized leuprolide acetate, the leuprolide acetatewill largely remain in suspension, thus requiring mixing with thepolymer-solvent system to ensure that a homogeneous suspension is formedprior to administration. The user then applies a force to the firstplunger disposed slidably within the first syringe to transfer thepartially to fully mixed components back through the open syringecoupler and into the second syringe. The user will continue mixing thecontents back and forth from the first and second syringes, in someinstances for about 1 minute, equivalent to approximately 60 fullback-and-forth cycles to ensure that the lyophilized leuprolide acetateis fully suspended within the polymer-solvent system. The fullyformulated composition is subsequently displaced into the second syringeat a final injection volume of about 0.375 mL and administeredformulation weight of about 375 mg. The user then disconnects the secondsyringe containing the therapeutic formulation from the syringe deviceby de-threading attachment to the male extension 54 upon thedisplaceable member 50 of the syringe connector. The user then attachesa needle, for example an 18G to 20G needle, to the distal dispensingoutlet of the second syringe. The user then subcutaneously administersthe formulation dose to an adult male prostate cancer patient in need oftreatment thereof.

According to the methods of administering the GnRH agonist or antagonistor a pharmaceutically acceptable salt thereof to a patient with prostatecancer using the syringe device system disclosed herein, the methodcomprises subcutaneously administering at least one injection of apharmaceutic composition comprising a unit dose of a GnRH agonist orantagonist or a pharmaceutically acceptable salt thereof, once everythree months (once per three months), to the patient to suppress thepatient's serum testosterone level to less than or equal to 0.5 ng/ml.Prior to the administering, the pharmaceutic composition isreconstituted using the syringe device system comprising a first syringebarrel comprising the GnRH agonist or antagonist or a pharmaceuticallyacceptable salt thereof and a second syringe barrel comprising a liquidformulation component, the first and second syringe barrels beinginterconnected via a syringe coupler comprising a displaceable seal,wherein the displaceable seal being operable to be axially displacedfrom a first position to a second position by a force applied to aplunger of the first syringe barrel, and wherein the first positioncomprises a position in which material transfer through the syringecoupler is occluded, and the second position comprises a position inwhich at least a portion of the displaceable seal is not secured to aninterior surface of the syringe coupler and material transfer throughthe syringe coupler is permitted. The pharmaceutic composition isreconstituted by applying a force to a user-interface to move thedisplaceable seal from the first position to the second position andapplying force to a plunger positioned in the first syringe barrel and aplunger positioned in the second syringe barrel in an alternating mannerto mix contents of the first syringe barrel and the second syringebarrel. In some instances, the GnRH agonist or antagonist or thepharmaceutically acceptable salt thereof is leuprolide or apharmaceutically acceptable salt thereof, such as leuprolide acetate. Insome instances, the GnRH agonist or antagonist or the pharmaceuticallyacceptable salt thereof is leuprolide or a pharmaceutically acceptablesalt thereof, such as leuprolide acetate. In some instances, thepharmaceutical composition comprises about 22.5 mg of leuprolide acetateand N-methyl-2-pyrrolidone, and a 75:25 poly(lactide-co-glycolide) (PLG)copolymer having a weight average molecular weight from about 17 kDa toabout 21 kDa and end groups that are hydroxyl-terminated as the liquidformulation component.

In yet another embodiment, a syringe device system comprises acomposition, which when formulated according to the methods of using thesyringe device system as described herein to intermix two separatedcomponents of the composition prior to administration, may be useful inthe palliative treatment of prostate cancer, including the palliativetreatment of advanced prostate cancer in an adult male patient, whenadministered by subcutaneous injection about once every four months(once per four months) to reduce the patient's serum testosterone levelto less than or equal to 0.5 ng/mL. According to this embodiment, thesyringe device system comprises a first syringe containing an amount ofa GnRH agonist or antagonist or a pharmaceutically acceptable saltthereof. In some instances, the syringe device system comprises a firstsyringe containing an amount of lyophilized leuprolide or apharmaceutically acceptable salt thereof, such as lyophilized leuprolideacetate. In some instances, the amount of leuprolide or apharmaceutically acceptable salt thereof in the delivered reconstitutedproduct may be about 28.0 mg leuprolide free base equivalent. In someinstances, the amount of leuprolide acetate in the deliveredreconstituted product may be about 30.0 mg. According to thisembodiment, the syringe device system comprises a second syringecontaining an amount of a polymer-solvent system comprising an amount ofa biodegradable polymer, which in some instances is apoly(D,L-lactide-co-glycolide) (i.e. PLG) polymer formulation dissolvedin a biocompatible solvent, which in some instances is NMP. In someinstances, the biodegradable PLG polymer may comprise a lactide toglycolide ratio of about 75:25. In some instances, the PLG polymer maybe initiated with hexanediol. In some instances, the PLG polymer maycompromise a copolymer containing two primary hydroxyl end groups. Insome instances, the PLG polymer has a weight average molecular weightrange of about 17 kDa to about 21 kDa. In some instances, the amount ofPLG polymer in the delivered reconstituted product may be about 211.5mg. In some instances, the amount of NMP in the delivered reconstitutedproduct is about 258.5 mg.

According to the methods of activating the syringe device system, asdisclosed herein, the user, after first allowing the pre-assembledsyringe device system to equilibrate to room temperature and thenremoving it from its packaging, applies force to the user-interfaceportions 52 and 57 of the displaceable member 50 and the guide member56, respectively, to activate the syringe coupler from the first closedposition to the second open position. The user then applies a force tothe second plunger disposed slidably within the second syringe totransfer the polymer-solvent system housed within the internal chamberof the second syringe barrel through the open, activated syringe couplerand into the internal chamber of the first syringe housing thelyophilized leuprolide acetate. Upon contact of the polymer-solventsystem with the lyophilized leuprolide acetate, the leuprolide acetatewill largely remain in suspension, thus requiring mixing with thepolymer-solvent system to ensure that a homogeneous suspension is formedprior to administration. The user then applies a force to the firstplunger disposed slidably within the first syringe to transfer thepartially to fully mixed components back through the open syringecoupler and into the second syringe. The user will continue mixing thecontents back and forth from the first and second syringes, in someinstances for about 1 minute, equivalent to approximately 60 fullback-and-forth cycles to ensure that the lyophilized leuprolide acetateis fully suspended within the polymer-solvent system. The fullyformulated composition is subsequently displaced into the second syringeat a final injection volume of about 0.5 mL and administered formulationweight of about 500 mg. The user then disconnects the second syringecontaining the therapeutic formulation from the syringe device byde-threading attachment to the male extension 54 upon the displaceablemember 50 of the syringe connector. The user then attaches a needle, forexample an 18G to 20G needle, to the distal dispensing outlet of thesecond syringe. The user then subcutaneously administers the fullformulation dose to an adult male prostate cancer patient in need oftreatment thereof.

According to the methods of administering the GnRH agonist or antagonistor a pharmaceutically acceptable salt thereof to a patient with prostatecancer using the syringe device system disclosed herein, the methodcomprises subcutaneously administering at least one injection of apharmaceutic composition comprising a unit dose of a GnRH agonist orantagonist or a pharmaceutically acceptable salt thereof, once everyfour months (once per four months), to the patient to suppress thepatient's serum testosterone level to less than or equal to 0.5 ng/ml.Prior to the administering, the pharmaceutic composition isreconstituted using the syringe device system comprising a first syringebarrel comprising the GnRH agonist or antagonist or a pharmaceuticallyacceptable salt thereof and a second syringe barrel comprising a liquidformulation component, the first and second syringe barrels beinginterconnected via a syringe coupler comprising a displaceable seal,wherein the displaceable seal being operable to be axially displacedfrom a first position to a second position by a force applied to aplunger of the first syringe barrel, and wherein the first positioncomprises a position in which material transfer through the syringecoupler is occluded, and the second position comprises a position inwhich at least a portion of the displaceable seal is not secured to aninterior surface of the syringe coupler and material transfer throughthe syringe coupler is permitted. The pharmaceutic composition isreconstituted by applying a force to a user-interface to move thedisplaceable seal from the first position to the second position andapplying force to a plunger positioned in the first syringe barrel and aplunger positioned in the second syringe barrel in an alternating mannerto mix contents of the first syringe barrel and the second syringebarrel. In some instances, the GnRH agonist or antagonist or thepharmaceutically acceptable salt thereof is leuprolide or apharmaceutically acceptable salt thereof, such as leuprolide acetate. Insome instances, the GnRH agonist or antagonist or the pharmaceuticallyacceptable salt thereof is leuprolide or a pharmaceutically acceptablesalt thereof, such as leuprolide acetate. In some instances, thepharmaceutical composition comprises about 30 mg of leuprolide acetateand N-methyl-2-pyrrolidone, and a 75:25 poly(lactide-co-glycolide) (PLG)copolymer having a weight average molecular weight from about 17 kDa toabout 21 kDa and end groups that are hydroxyl-terminated as the liquidformulation component.

In yet another embodiment of the invention, the syringe device systemcomprises a composition, which when formulated according to the methodsof using the syringe device system as described herein to intermix twoseparated components of the composition prior to administration, may beuseful in the palliative treatment of prostate cancer, including thepalliative treatment of advanced prostate cancer in an adult malepatient, when administered by subcutaneous injection about once everysix months (once per six months) to reduce the patient's serumtestosterone level to less than or equal to 0.5 ng/mL. According to thisembodiment, the syringe device system comprises a first syringecontaining an amount of a GnRH agonist or antagonist or apharmaceutically acceptable salt thereof. In some instances, the syringedevice system comprises a first syringe containing an amount oflyophilized leuprolide or a pharmaceutically acceptable salt thereof,such as lyophilized leuprolide acetate. In some instances, the amount ofleuprolide or a pharmaceutically acceptable salt thereof in thedelivered reconstituted product may be about 42.0 mg leuprolide freebase equivalent. In some instances, the amount of leuprolide acetate inthe delivered reconstituted product may be about 45.0 mg. According tothis embodiment, the syringe device system comprises a second syringecontaining an amount of a polymer-solvent system comprising an amount ofa biodegradable polymer, which in some instances is apoly(D,L-lactide-co-glycolide) (i.e. PLG) polymer formulation dissolvedin a biocompatible solvent, which in some instances is NMP. In someinstances, the biodegradable PLG polymer may comprise a lactide toglycolide ratio of about 85:15. In some instances, the PLG polymer maybe initiated with hexanediol. In some instances, the PLG polymer maycompromise a copolymer containing two primary hydroxyl end groups. Insome instances, the PLG polymer has a weight average molecular weightrange of about 20 kDa to about 26 kDa. In some instances, the amount ofPLG polymer in the delivered reconstituted product may be about 165 mg.In some instances, the amount of NMP in the delivered reconstitutedproduct is about 165 mg.

According to the methods of activating the syringe device system, asdisclosed herein, the user, after first allowing the pre-assembledsyringe device system to equilibrate to room temperature and thenremoving it from its packaging, applies force to the user-interfaceportions 52 and 57 of the displaceable member 50 and the guide member56, respectively, to activate the syringe coupler from the first closedposition to the second open position. The user then applies a force tothe second plunger disposed slidably within the second syringe totransfer the polymer-solvent system housed within the internal chamberof the second syringe barrel through the open, activated syringe couplerand into the internal chamber of the first syringe housing thelyophilized leuprolide acetate. Upon contact of the polymer-solventsystem with the lyophilized leuprolide acetate, the leuprolide acetatewill largely remain in suspension, thus requiring mixing with thepolymer-solvent system to ensure that a homogeneous suspension is formedprior to administration. The user then applies a force to the firstplunger disposed slidably within the first syringe to transfer thepartially to fully mixed components back through the open syringecoupler and into the second syringe. The user will continue mixing thecontents back and forth from the first and second syringes, in someinstances for about 1 minute, equivalent to approximately 60 fullback-and-forth cycles to ensure that the lyophilized leuprolide acetateis fully suspended within the polymer-solvent system. The fullyformulated composition is subsequently displaced into the second syringeat a final injection volume of about 0.375 mL and administeredformulation weight of about 375 mg. The user then disconnects the secondsyringe containing the therapeutic formulation from the syringe deviceby de-threading attachment to the male extension 54 upon thedisplaceable member 50 of the syringe connector. The user then attachesa needle, for example an 18G to 20G needle, to the distal dispensingoutlet of the second syringe. The user then subcutaneously administersthe full formulation dose to an adult male prostate cancer patient inneed of treatment thereof.

According to the methods of administering the GnRH agonist or antagonistor a pharmaceutically acceptable salt thereof to a patient with prostatecancer using the syringe device system disclosed herein, the methodcomprises subcutaneously administering at least one injection of apharmaceutic composition comprising a unit dose of a GnRH agonist orantagonist or a pharmaceutically acceptable salt thereof, once every sixmonths (once per six months), to the patient to suppress the patient'sserum testosterone level to less than or equal to 0.5 ng/ml. Prior tothe administering, the pharmaceutic composition is reconstituted usingthe syringe device system comprising a first syringe barrel comprisingthe GnRH agonist or antagonist or a pharmaceutically acceptable saltthereof and a second syringe barrel comprising a liquid formulationcomponent, the first and second syringe barrels being interconnected viaa syringe coupler comprising a displaceable seal, wherein thedisplaceable seal being operable to be axially displaced from a firstposition to a second position by a force applied to a plunger of thefirst syringe barrel, and wherein the first position comprises aposition in which material transfer through the syringe coupler isoccluded, and the second position comprises a position in which at leasta portion of the displaceable seal is not secured to an interior surfaceof the syringe coupler and material transfer through the syringe coupleris permitted. The pharmaceutic composition is reconstituted by applyinga force to a user-interface to move the displaceable seal from the firstposition to the second position and applying force to a plungerpositioned in the first syringe barrel and a plunger positioned in thesecond syringe barrel in an alternating manner to mix contents of thefirst syringe barrel and the second syringe barrel. In some instances,the GnRH agonist or antagonist or the pharmaceutically acceptable saltthereof is leuprolide or a pharmaceutically acceptable salt thereof,such as leuprolide acetate. In some instances, the GnRH agonist orantagonist or the pharmaceutically acceptable salt thereof is leuprolideor a pharmaceutically acceptable salt thereof, such as leuprolideacetate. In some instances, the pharmaceutical composition comprisesabout 45 mg of leuprolide acetate and N-methyl-2-pyrrolidone, and an85:15 poly(lactide-co-glycolide) (PLG) copolymer having a weight averagemolecular weight from about 20 kDa to about 26 kDa and end groups thatare hydroxyl-terminated as the liquid formulation component.

In yet another embodiment, a syringe device system comprises acomposition, which when formulated according to the methods of using thesyringe device system as described herein to intermix two separatedcomponents of the composition prior to administration, may be useful insuppressing ovarian function in a patient with HR-positive breastcancer. The composition may further be useful in suppressing one or moreof the patient's estradiol (E2) level to less than 20 pg/mL, thepatient's follicle stimulating hormone (FSH) level to less than 40 IU/L,and patient's mean serum luteinizing hormone (LH) level. In someinstances, the composition may be administered concurrently with one ormore other therapeutic treatments for HR-positive breast cancer,including, but not limited to endocrine therapy, chemotherapy, and/orradiotherapy. In some instances, the composition is administered bysubcutaneous injection about once every three months (once per threemonths). According to this embodiment, the syringe device systemcomprises a first syringe containing an amount of a GnRH agonist orantagonist or a pharmaceutically acceptable salt thereof. In someinstances, the syringe device system comprises a first syringecontaining an amount of lyophilized leuprolide or a pharmaceuticallyacceptable salt thereof, such as lyophilized leuprolide acetate. In someinstances, the amount of leuprolide or a pharmaceutically acceptablesalt thereof in the delivered reconstituted product may be about 26 mgto about 30 mg, preferably 28 mg leuprolide free base equivalent. Insome instances, the amount of leuprolide acetate in the deliveredreconstituted product may be about 28 mg to about 32 mg, preferably 30mg. According to this embodiment, the syringe device system comprises asecond syringe containing an amount of a polymer-solvent systemcomprising an amount of a biodegradable polymer, which in some instancesis a poly(D,L-lactide-co-glycolide) (i.e. PLG) polymer formulationdissolved in a biocompatible solvent, which in some instances is NMP. Insome instances, the biodegradable PLG polymer may comprise a lactide toglycolide ratio of about 70:30 to about 80:20, preferably about 75:25.In some instances, the PLG polymer may be initiated with hexanediol. Insome instances, the PLG polymer may compromise a copolymer containingtwo primary hydroxyl end groups. In some instances, the PLG polymer maybe initiated with dodecanol. In some instances, the PLG polymer maycompromise a copolymer containing a hydroxyl end group and an ester endgroup. In some instances, the PLG polymer has a weight average molecularweight range of about 15 kDa to about 45 kDa, preferably about 17 kDa toabout 21 kDa. In some instances, the amount of PLG polymer in thedelivered reconstituted product may be about 158.6 mg. In someinstances, the amount of NMP in the delivered reconstituted product isabout 193.9 mg.

According to the methods of activating the syringe device system, asdisclosed herein, the user, after first allowing the pre-assembledsyringe device system to equilibrate to room temperature and thenremoving it from its packaging, applies force to the user-interfaceportions 52 and 57 of the displaceable member 50 and the guide member56, respectively, to activate the syringe coupler from the first closedposition to the second open position. The user then applies a force tothe second plunger disposed slidably within the second syringe totransfer the polymer-solvent system housed within the internal chamberof the second syringe barrel through the open, activated syringe couplerand into the internal chamber of the first syringe housing thelyophilized leuprolide acetate. Upon contact of the polymer-solventsystem with the lyophilized leuprolide acetate, the leuprolide acetatewill largely remain in suspension, thus requiring mixing with thepolymer-solvent system to ensure that a homogeneous suspension is formedprior to administration. The user then applies a force to the firstplunger disposed slidably within the first syringe to transfer thepartially to fully mixed components back through the open syringecoupler and into the second syringe. The user will continue mixing thecontents back and forth from the first and second syringes, in someinstances for about 1 minute, equivalent to approximately 60 fullback-and-forth cycles to ensure that the lyophilized leuprolide acetateis fully suspended within the polymer-solvent system. The fullyformulated composition is subsequently displaced into the second syringeat a final injection volume of about 0.375 mL and administeredformulation weight of about 375 mg to about 400 mg. The user thendisconnects the second syringe containing the therapeutic formulationfrom the syringe device by de-threading attachment to the male extension54 upon the displaceable member 50 of the syringe connector. The userthen attaches a needle, for example a 18G to 20G needle, to the distaldispensing outlet of the second syringe. The user then subcutaneouslyadministers the full formulation dose to an adult breast cancer patientin need of treatment thereof.

According to the methods of administering the GnRH agonist or antagonistor a pharmaceutically acceptable salt thereof to a patient with hormonereceptor-positive breast cancer using the syringe device systemdisclosed herein, the method comprises subcutaneously administering atleast one injection of a pharmaceutic composition comprising a unit doseof a GnRH agonist or antagonist or a pharmaceutically acceptable saltthereof, once every three months (once per three months), to the patientto suppress the patient's ovarian function. In some instances,administering the at least one injection of the pharmaceutic compositioncomprising a unit dose of a GnRH agonist or antagonist or apharmaceutically acceptable salt thereof, once every three months, tothe patient suppresses one or more of the patient's estradiol (E2) levelto less than 20 pg/mL, the patient's follicle stimulating hormone (FSH)level to less than 40 IU/L, and patient's mean serum luteinizing hormone(LH) level. Prior to the administering, the pharmaceutic composition isreconstituted using the syringe device system comprising a first syringebarrel comprising the GnRH agonist or antagonist or a pharmaceuticallyacceptable salt thereof and a second syringe barrel comprising a liquidformulation component, the first and second syringe barrels beinginterconnected via a syringe coupler comprising a displaceable seal,wherein the displaceable seal being operable to be axially displacedfrom a first position to a second position by a force applied to aplunger of the first syringe barrel, and wherein the first positioncomprises a position in which material transfer through the syringecoupler is occluded, and the second position comprises a position inwhich at least a portion of the displaceable seal is not secured to aninterior surface of the syringe coupler and material transfer throughthe syringe coupler is permitted. The pharmaceutic composition isreconstituted by applying a force to a user-interface to move thedisplaceable seal from the first position to the second position andapplying force to a plunger positioned in the first syringe barrel and aplunger positioned in the second syringe barrel in an alternating mannerto mix contents of the first syringe barrel and the second syringebarrel. In some instances, the GnRH agonist or antagonist or thepharmaceutically acceptable salt thereof is leuprolide or apharmaceutically acceptable salt thereof, such as leuprolide acetate. Insome instances, the pharmaceutical composition comprises about 30 mg ofleuprolide acetate and N-methyl-2-pyrrolidone and a 75:25poly(lactide-co-glycolide) (PLG) copolymer having a weight averagemolecular weight from about 17 kDa to about 21 kDa and one distal endgroup that is hydroxyl-terminated and the other distal end group that iseither hydroxyl-terminated or ester-terminated as the liquid formulationcomponent.

In yet another embodiment of the invention, the syringe device systemcomprises a composition, which when formulated according to the methodsof using the syringe device system as described herein to intermix twoseparated components of the composition prior to administration, may beuseful in the treatment of CPP in a pediatric patient 2 years of age orolder, when administered by subcutaneous injection about once every sixmonths (once per six months) to reduce the pediatric patient's peakstimulated blood serum LH concentration to a pre-pubertal concentrationlevel of less than 4 IU/L. According to this embodiment, the syringedevice system comprises a first syringe containing an amount of a GnRHagonist or antagonist or a pharmaceutically acceptable salt thereof. Insome instances, the syringe device system comprises a first syringecontaining an amount of lyophilized leuprolide or a pharmaceuticallyacceptable salt thereof, such as lyophilized leuprolide acetate. In someinstances, the amount of leuprolide or a pharmaceutically acceptablesalt thereof in the delivered reconstituted product may be about 42.0 mgleuprolide free base equivalent. In some instances, the amount ofleuprolide acetate in the delivered reconstituted product may be about45.0 mg. According to this embodiment, the syringe device systemcomprises a second syringe containing an amount of a polymer-solventsystem comprising an amount of a biodegradable polymer, which in someinstances is a poly(D,L-lactide-co-glycolide) (i.e. PLG) polymerformulation dissolved in a biocompatible solvent, which in someinstances is NMP. In some instances, the biodegradable PLG polymer maycomprise a lactide to glycolide ratio of about 85:15. In some instances,the PLG polymer may be initiated with hexanediol. In some instances, thePLG polymer may compromise a copolymer containing two primary hydroxylend groups. In some instances, the PLG polymer may be initiated withdodecanol. In some instances, the PLG polymer may compromise a copolymercontaining a hydroxyl end group and an ester end group. In someinstances, the PLG polymer has a weight average molecular weight rangeof about 20 kDa to about 26 kDa. In some instances, the amount of PLGpolymer in the delivered reconstituted product may be about 165 mg. Insome instances, the amount of NMP in the delivered reconstituted productis about 165 mg.

According to the methods of activating the syringe device system, asdisclosed herein, the user, after first allowing the pre-assembledsyringe device system to equilibrate to room temperature and thenremoving it from its packaging, applies force to the user-interfaceportions 52 and 57 of the displaceable member 50 and the guide member56, respectively, to activate the syringe coupler from the first closedposition to the second open position. The user then applies a force tothe second plunger disposed slidably within the second syringe totransfer the polymer-solvent system housed within the internal chamberof the second syringe barrel through the open, activated syringe couplerand into the internal chamber of the first syringe housing thelyophilized leuprolide acetate. Upon contact of the polymer-solventsystem with the lyophilized leuprolide acetate, the leuprolide acetatewill largely remain in suspension, thus requiring mixing with thepolymer-solvent system to ensure that a homogeneous suspension is formedprior to administration. The user then applies a force to the firstplunger disposed slidably within the first syringe to transfer thepartially to fully mixed components back through the open syringecoupler and into the second syringe. The user will continue mixing thecontents back and forth from the first and second syringes, in someinstances for about 1 minute, equivalent to approximately 60 fullback-and-forth cycles to ensure that the lyophilized leuprolide acetateis fully suspended within the polymer-solvent system. The fullyformulated composition is subsequently displaced into the second syringeat a final injection volume of about 0.375 mL and administeredformulation weight of about 375 mg. The user then disconnects the secondsyringe containing the therapeutic formulation from the syringe deviceby de-threading attachment to the male extension 54 upon thedisplaceable member 50 of the syringe connector. The user then attachesa needle, for example an 18G to 20G needle, to the distal dispensingoutlet of the second syringe. The user then subcutaneously administersthe full formulation dose to a pediatric patient 2 years of age or olderin need of treatment thereof.

According to the methods of administering the GnRH agonist or antagonistor a pharmaceutically acceptable salt thereof to a pediatric patient 2years of age or older with central precocious puberty (CPP) using thesyringe device system disclosed herein, the method comprisessubcutaneously administering at least one injection of a pharmaceuticcomposition comprising a unit dose of a GnRH agonist or antagonist or apharmaceutically acceptable salt thereof, once every six months (onceper six months), to the pediatric patient to reduce the pediatricpatient's peak stimulated blood serum LH concentration to a pre-pubertalconcentration of less than 4 IU/L. Prior to the administering, thepharmaceutic composition is reconstituted using the syringe devicesystem comprising a first syringe barrel comprising the GnRH agonist orantagonist or a pharmaceutically acceptable salt thereof and a secondsyringe barrel comprising a liquid formulation component, the first andsecond syringe barrels being interconnected via a syringe couplercomprising a displaceable seal, wherein the displaceable seal beingoperable to be axially displaced from a first position to a secondposition by a force applied to a plunger of the first syringe barrel,and wherein the first position comprises a position in which materialtransfer through the syringe coupler is occluded, and the secondposition comprises a position in which at least a portion of thedisplaceable seal is not secured to an interior surface of the syringecoupler and material transfer through the syringe coupler is permitted.The pharmaceutic composition is reconstituted by applying a force to auser-interface to move the displaceable seal from the first position tothe second position and applying force to a plunger positioned in thefirst syringe barrel and a plunger positioned in the second syringebarrel in an alternating manner to mix contents of the first syringebarrel and the second syringe barrel. In some instances, the GnRHagonist or antagonist or the pharmaceutically acceptable salt thereof isleuprolide or a pharmaceutically acceptable salt thereof, such asleuprolide acetate. In some instances, the pharmaceutical compositioncomprises about 45 mg of leuprolide acetate and N-methyl-2-pyrrolidoneand an 85:15 poly(lactide-co-glycolide) (PLG) copolymer having a weightaverage molecular weight from about 20 kDa to about 26 kDa and onedistal end group that is hydroxyl-terminated and the other distal endgroup that is either hydroxyl-terminated or ester-terminated as theliquid formulation component.

Various features and embodiments of a pre-connected syringe-to-syringedevice and system and methods of using the pre-connectedsyringe-to-syringe device have been provided herein. It will berecognized, however, that various features are not necessarily specificto certain embodiments and may be provided on any one or moreembodiments. The present disclosure and embodiments provided herein arenot mutually exclusive and may be combined, substituted, and omitted.The scope of the invention(s) provided herein is thus not limited to anyparticular embodiment, drawing, or particular arrangement of features.

While various embodiments of the present disclosure have been describedin detail, it is apparent that modifications and alterations of thoseembodiments will occur to those skilled in the art. However, it is to beexpressly understood that such modifications and alterations are withinthe scope and spirit of the present disclosure. Further, theinvention(s) described herein are capable of other embodiments and ofbeing practiced or of being carried out in various ways. In addition, itis to be understood that the phraseology and terminology used herein isfor the purposes of description and should not be regarded as limiting.The use of “including,” “comprising,” or “adding” and variations thereofherein are meant to encompass the items listed thereafter andequivalents thereof, as well as, additional items.

What is claimed is:
 1. A syringe-to-syringe mixing system comprising: afirst syringe barrel comprising a hollow body, the hollow body having aproximal end and a distal dispensing end with an outlet; a secondsyringe barrel comprising a hollow body and an outlet, the secondsyringe comprising a distal dispensing end with an outlet; the firstsyringe barrel and the second syringe barrel each comprising a plungerslidably disposed within the syringe barrel for applying pressure to asyringe content housed within the internal chambers; a valve assemblythat is operable to receive the first syringe barrel and the secondsyringe barrel, and wherein the valve assembly comprises at least oneresilient member that is biased toward a locked position; wherein thevalve assembly comprises a displaceable user-interface operable toreceive a force from a user and transmit the force to a displaceableseal, and wherein the displaceable user-interface and the displaceableseal are moveable in a direction substantially perpendicular to alongitudinal axis of at least one of the first syringe barrel and thesecond syringe barrel; and wherein the valve assembly comprises a firstposition wherein a fluid flow between the first syringe barrel and thesecond syringe barrel is fully occluded, and a second position in whichfluid is allowed to flow between the first syringe barrel and the secondsyringe barrel.
 2. The syringe-to-syringe mixing system of claim 1,wherein at least one of the first syringe barrel and the second syringebarrel is moveable with the valve assembly.
 3. The syringe-to-syringemixing system of claim 1, wherein one of the first syringe barrel andthe second syringe barrel comprises a drug and wherein the other syringebarrel comprises a liquid formulation component.
 4. Thesyringe-to-syringe mixing system of claim 1, wherein at least one of thefirst syringe barrel and the second syringe barrel comprise leuprolideacetate.
 5. The syringe-to-syringe mixing system of claim 1, wherein thevalve assembly comprises a first syringe-receiving member and a secondsyringe-receiving member, wherein at least one of the firstsyringe-receiving member and the second syringe-receiving membercomprises a threaded member that is substantially prevented fromrotating relative to the valve assembly when the displaceableuser-interface is provided in a first position and the threaded memberis free to rotate when the displaceable user-interface is provided in asecond position.
 6. A syringe coupler that is operable to receive afirst syringe barrel and a second syringe barrel associated with asyringe mixing system, the syringe coupler comprising: a displaceablemember operable to be selectively contacted by a user to convert thesyringe coupler from a first position to a second position; a seal witha flow port that is moveable with the displaceable member; a firstsyringe receiving-member and a second syringe-receiving member, whereinat least one of the first syringe-receiving member and the secondsyringe-receiving member comprises a threaded member; wherein thethreaded member is substantially prevented from rotating relative to thesyringe coupler when the displaceable member is provided in the firstposition; and wherein the threaded member is freely rotatable when thedisplaceable member is provided in the second position.
 7. The syringecoupler of claim 6, wherein the first position comprises a closedposition in which fluid flow through the coupler is occluded and whereinthe second position comprises an open position in which fluid flowthrough the coupler is enabled.
 8. The syringe coupler of claim 6,wherein the threaded member further comprises a contact surface operableto be engaged by a portion of the syringe coupler when the syringecoupler is provided in the first position.
 9. The syringe coupler ofclaim 6, wherein the threaded member comprises a flow port, and whereinthe flow port of the seal and the flow port of the threaded member areoffset relative to one another in the first position.
 10. The syringecoupler of claim 6, wherein the threaded member comprises a flow port,and wherein the flow port of the seal and the flow port of the threadedmember are aligned in the second position.
 11. The syringe coupler ofclaim 6, wherein the syringe coupler comprises at least one resilientmember to secure the syringe coupler in the second position andsubstantially prevent the syringe coupler from returning to the firstposition.
 12. The syringe coupler of claim 6, wherein the first syringereceiving-member and the second syringe-receiving member each compriseLuer lock members that are operable to receive a distal end of asyringe.
 13. The syringe coupler of claim 6, further comprising a firstsyringe and a second syringe secured to the syringe coupler.
 14. Thesyringe coupler of claim 13, wherein at least one of the first syringeand the second syringe comprises lyophilized leuprolide acetate.
 15. Asyringe-to-syringe mixing system comprising: a first syringe barrelcomprising a hollow body defining an internal chamber, the hollow bodyhaving a proximal end and a distal dispensing end with an outlet; asecond syringe barrel comprising a hollow body defining an internalchamber, the hollow body of the second syringe barrel having a proximalend and a distal dispensing end with an outlet; the first syringe barreland the second syringe barrel each comprising a plunger slidablydisposed within the syringe barrel for applying pressure to a syringecontent housed within the internal chambers; a syringe coupler that isoperable to receive the first syringe barrel and the second syringebarrel; the syringe coupler comprising a displaceable member, whereinthe displaceable member comprises a seal with a flow port that is offsetfrom the outlet of at least one of the first syringe barrel and thesecond syringe barrel when the displaceable member is provided in afirst position, and wherein the flow port is aligned with the outlet ofthe first syringe barrel and the second syringe barrel when thedisplaceable member is provided in a second position.
 16. Thesyringe-to-syringe mixing system of claim 15, wherein the syringecoupler comprises a user-interface operable to receive a force from auser and transmit the force to the seal.
 17. The syringe-to-syringemixing system of claim 15, wherein the displaceable member isdisplaceable in a direction that is substantially perpendicular to alongitudinal axis of at least one of the first syringe barrel and thesecond syringe barrel.
 18. The syringe-to-syringe mixing system of claim15, wherein the syringe coupler comprises a rotatable Luer lock memberthat is free to rotate within the syringe coupler when the displaceablecoupler is provided in the second position.
 19. The syringe-to-syringemixing system of claim 15, wherein at least one of the first syringebarrel and the second syringe barrel comprise leuprolide acetate. 20.The syringe-to-syringe mixing system of claim 15, wherein theuser-interface comprises at least one resilient projection that isbiased toward a locked position.
 21. The syringe-to-syringe mixingsystem of claim 1, wherein the pharmaceutical composition comprisesabout 7.5 mg of leuprolide acetate as the active pharmaceuticalingredient and N-methyl-2-pyrrolidone and a 50:50 poly(lacticacid-co-glycolic acid) (PLGA) copolymer having a weight averagemolecular weight from about 31 kDa to about 45 kDa and at least oneterminal carboxylic acid end group as the liquid formulation component.22. The syringe-to-syringe mixing system of claim 1, wherein thepharmaceutical composition comprises about 22.5 mg of leuprolide acetateas the active pharmaceutical ingredient and N-methyl-2-pyrrolidone, anda 75:25 poly(lactide-co-glycolide) (PLG) copolymer having a weightaverage molecular weight from about 17 kDa to about 21 kDa and endgroups that are hydroxyl-terminated as the liquid formulation component.23. The syringe-to-syringe mixing system of claim 1, wherein thepharmaceutical composition comprises about 30 mg of leuprolide acetateas the active pharmaceutical ingredient and N-methyl-2-pyrrolidone, anda 75:25 poly(lactide-co-glycolide) (PLG) copolymer having a weightaverage molecular weight from about 17 kDa to about 21 kDa and onedistal end group that is hydroxyl-terminated and the other distal endgroup that is either hydroxyl-terminated or ester-terminated as theliquid formulation component.
 25. The syringe-to-syringe mixing systemof claim 1, wherein the pharmaceutical composition comprises about 45 mgof leuprolide acetate as the active pharmaceutical ingredient andN-methyl-2-pyrrolidone, and an 85:15 poly(lactide-co-glycolide) (PLG)copolymer having a weight average molecular weight from about 20 kDa toabout 26 kDa and one distal end group that is hydroxyl-terminated andthe other distal end group that is either hydroxyl-terminated orester-terminated as the liquid formulation component.